Current Topics in Medicinal Chemistry, 2008, 8, 1555-1572 1555

Medicinal Chemistry and the Molecular Operating Environment (MOE):

Application of QSAR and Molecular Docking to Drug Discovery
Santiago Vilar*†‡, Giorgio Cozza‡ and Stefano Moro‡
Faculty of Pharmacy, Department of Organic Chemistry, University of Santiago de Compostela, Santiago de
Compostela 15782, Spain, Molecular Modeling Section, Dipartimento di Scienze Farmaceutiche, Università di Padova,
Via Marzolo 5, Padova, Italy

Abstract: The search for new compounds with a given biological activity requires enormous effort in terms of manpower
and cost. This effort arises from the large number of compounds that need to be synthesized and subsequently biologically
evaluated. For this reason the pharmaceutical industry has shown great interest in theoretical methods that enable the
rational design of pharmaceutical agents. In the last years bioinformatics has experienced a great evolution due to the
development of specialized software and to the increasing computer power. The codification of the structural information
of molecules through molecular descriptors and the subsequent data analysis allow establishing QSAR models
(Quantitative Structure-Activity Relationship) that can be applied to the design and the virtual screening of new drugs.
The development of sophisticated Docking methodologies also allows a more accurate predict of the biological activity of
molecules. Moreover, through this type of computational techniques and theoretical approaches, it is possible to develop
explanatory hypothesis on the mechanism of action of drugs. This work provides a brief description of a series of studies
implemented in the software MOE (Molecular Operating Environment) with particular attention to the medicinal
chemistry aspects.
Keywords: QSAR, Docking, Molecular Descriptors, Statistical Analysis, MOE.

INTRODUCTION search, like molecular dynamics [23, 24] or MonteCarlo

Quantitative structure-activity relationships (QSAR)
studies have acquired an important position within modern
chemistry [1-9]. In QSAR analysis, one or more molecular
descriptors are related with the molecular activity by means
of a statistical analysis. The main objective of this analysis is
the creation of statistical models through which it is possible
to predict the biological activity of novel compounds that
have not been tested yet. Also, through a QSAR study one
can give a mechanistic interpretation to the activity of a
certain family of compounds and direct their optimization.
The main steps involved in the development of a QSAR
model are the selection of the database of compounds with
known biological activities (training set), the calculation of
molecular descriptors, the development of a statistical model
that relates the activity with the calculated descriptors and,
later, the evaluation of the generated model with a test set
(see Fig. (1)).
The molecular descriptors consist in a series of numerical
values associated, for example, with the structural,
electronic, steric, or physico-chemical properties of the
molecular system in study. At the present, a great number of
molecular descriptors have been conceived among which,
topological indices [10-12], as well as quantum chemicals
[13, 14], topographics [15, 16], and physical-chemicals
descriptors [17]. For the calculation of the topographic and
quantum-chemical descriptors it is necessary to determine
the most stable 3D structure of the compounds through
molecular mechanics [18-20] or semiempirical calculations
[21, 22] in combination with methods of conformacional
*Address correspondence to this author at the Faculty of Pharmacy,
Department of Organic Chemistry, University of Santiago de Compostela,
Santiago de Compostela 15782, Spain; Fax: +34-981-594912;
E-mail: qosanti@yahoo.es
simulations [25]. Despite these difficulties, the calculation of
topological descriptors has experienced a strong develop-
ment in the last years, since, through simple procedures, they
allow an effective codification of the structural information
of a molecule.
Also, a variety of statistical methodologies applicable to
chemometrical analysis exists, like Multiple Linear Regres-
sion (MLR), Linear Discriminant Analysis (LDA), Partial
Least Squares regression (PLS), Principal Component
Analysis (PCA), and different types of Artificial Neural
Networks (ANN). These techniques can effectively be used
to establish a correlation model between the molecular struc-
tures (molecular descriptors) and the associated properties
[26-34].
Another way of studying the interaction between a drug
and a specific biological receptor consists in modeling the
molecular complex formed by the two molecules. The three-
dimensional structures of a number of drug-protein
complexes have been determined by X-ray spectroscopy and
Nuclear Magnetic Resonance. These experimental structures
provide a very useful high resolution representation of the
active site of the proteins and of their interactions with
ligands. On the basis of this structural information it is
possible to design new compounds endowed with a higher
affinity for the target. However, structure-based drug design
gets significantly more complicated when the structure of the
proteins have not been determined experimentally, in which
case one has to rely on experimentally-supported homology
models.
Macromolecule-ligand complexes can be obtained by
means of molecular docking experiments, conducted using
experimental structures or homology models. Different
docking methodologies and different scoring functions have

1568-0266/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd.

1556 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18
Compounds sampling
Database
Molecular Description
Molecular Parameters
Mathematical Analysis
Quantitative structure-activity relationship
QSAR
Prediction
Fig. (1). Main Steps Involved in the Development of a QSAR Model.
been developed to estimate and to quantify the ligand-protein
interaction [35-38]. These structure-based techniques
revealed to be very useful to study molecular recognition
from a qualitative and quantitative point of view.
In this work we reviewed a series of recently published
articles in which the software MOE [39] has been used to
generate models based on the calculation of molecular
descriptors and statistical analysis (QSAR) and models based
on molecular docking.
1. MOLECULAR DESCRIPTORS AND QSAR WITH
MOE
By means of the QuaSAR-Descriptor application of
MOE it is possible to calculate a great number of molecular
descriptors. The calculated descriptors can be divided in
three classes: 2D descriptors (based only on atoms and
connectivity information); internal 3D descriptors (i3D,
based on 3D coordinate information but not affected by
orientation) and external 3D descriptors (x3D, based on 3D
coordinate information but sensitive to absolute orientation).
Some 2D descriptors are: physical properties, subdivided
surface areas, atoms counts and bond counts, Kier & Hall
connectivity and kappa shape indices, adjacency and dis-
tance matrix descriptors, pharmacophore feature descriptors,
and partial charge descriptors. 3D descriptors are classified
as potential energy descriptors, surface area, volume and
shape descriptors, and conformation dependent charge
descriptors. Additionally, news descriptors can be introduced
in MOE by means of the SVL function.
Vilar et al.
Biological assays
Biological Parameters
Interpretation
Once the descriptors have been calculated, it is possible
to carry out different types of statistical analysis such as
Binary QSAR, Principal Component Analysis (PCA), Partial
Least Squares (PLS), and Multiple Linear Regression
(MLR). In the following sections, we will describe in greater
detail these various aspects.
1.1. Calculation of Molecular Descriptors
Baraldi et al. [40] studied a series of pyrazolotriazolo-
pyrimidines (see Fig. 2, structure 1) which had been
previously reported [41] to be highly potent and selective
human A3 adenosine receptor antagonists. Molecular volume
and log P values (log of the octanol/water partition
coefficient), a hydrophobicity indicator, were empirically
calculated using the atom fragment method implemented in
the QuaSAR-Descriptor module of MOE [39]. They found a
significative correlation between the calculated molecular
volume of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine
derivatives and their experimental Ki values. In particular,
their affinities for the A3 receptor decrease with the
increasing molecular volume values at the N8 position.
Support Vector Machine (SVM) [42] and Artificial
Neural Network (ANN) [43] systems were applied to a
drug/nondrug classification problem with good results [44].
The performance was compared using different descriptor
sets and descriptor combinations chosen among the 120
standard Ghose-Crippen fragment descriptors [45, 46], 180
different properties and physicochemical descriptors
calculated with MOE, and 225 topological pharmacophore
(CATS) descriptors [47]. MOE descriptors include various
Medicinal Chemistry and the Molecular Operating Environment (MOE)
2D and 3D descriptors such as volume and shape descriptors,
atom and bonds counts, Kier-Hall connectivity and kappa
shape indices, adjacency and distance matrix descriptors,
pharmacophore feature descriptors, partial charges, potential
energy descriptors, and conformation-dependent charge
descriptors. A similar problem for drug/nondrug classifi-
cation was analyzed by means of ANN by Givehchi et al.
[48]. Two types of neural networks were used, supervised
multilayer neural nets [49] and unsupervised self-organizing
maps (Kohonen maps) [50]. 32 2D descriptors were
generated for each compound with MOE [39]. Data were
preprocessed by logistic scaling and histogram equalization.
The appropriate data preprocessing is an important step
because it significantly improved classification compared to
nonstandardized data and led to a reduced error rate. To
measure the classification accuracy, the authors calculated
prediction mean square error and Matthews correlation
coefficient for supervised learning, and quantization error for
unsupervised learning.
Xiao et al. have employed in parallel the Catalyst
HypoGen pharmacophore modeling approach and the
variable selection k-nearest neighbor quantitative structure–
activity relationship (kNN QSAR) method to model a diverse
data set of p38 mitogen-activated protein (MAP) kinase
inhibitors [51]. Molecular topological indices [52, 53] were
obtained with the MolConnZ program (MCI descriptors)
[54], while additional molecular descriptors were generated
with MOE. The Catalyst pharmacophore models identified
functional features important for p38 MAP kinase binding.
The kNN QSAR modeling afforded predictive QSAR models
with consistently high values of both leave-one-out cross-
validated R2 for the training set and predictive R2 for the test
set.
QSAR studies have been performed on a series of diaryl
furanones that acts as selective COX-2 inhibitor using MOE
[55]. The studies were carried out on 43 analogs, 31 used as
training set and 12 as test set (see Fig. (2), structure 2). All
the compounds were drawn with the builder module of
MOE. The compounds were then subjected to confor-
mational analysis and energy minimization. Descriptors were
calculated from the lowest energy conformer. By means of
MOE, 193 descriptors divided in three classes were
calculated—2D descriptors; i3D, internal 3D descriptors and
x3D, external 3D descriptors. The correlation between the
biological activity (pIC50) and the descriptors were
performed by stepwise regression analysis using QSAR easy
software [56], on yielded the followings equations:
pIC50 COX
2 = 1.281(Std_dim2) + (1)
1.719(Kier A3)-0.042(SlogP_vsa1) - 0.076
N = 31; r = 0.870; r2 = 0.757; adjusted r2 = 0.730; S = 0.432;
F3, 27 = 28.084
When 1 compound was considered outlier the equation
was:
pIC50 COX
2 = 0.921(Std_dim2) + (2)
1.919(Kier A3)-0.037(SlogP_vsa1) - 0.238
N = 30; r = 0.922; r2 = 0.849; adjusted r2 = 0.832; S = 0.339;
F3, 26 = 48.807
Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1557
where, Std_dim2 is three dimensional surface area, volume
and shape descriptor; Kier A3 is Kier and Hall Connectivity
and Kappa Shape Index; SlogP_vsa1 is subdivided surface
area descriptor based on sum of the approximate accessible
van der Waal’s surface area calculated for each atom with
contribution to log of partition coefficient (octanol/water).
A discriminant model constructed by means of the SVM
method for HERG potassium channel inhibitors was reported
by Tobita et al. [57]. The therapeutic categories common to
HERG (human ether-a-go-go related gene) inhibitors include
antiarrhythmics, antipsychotics, antihistamines, opioid
blockers, and Ca2+ blockers [58]. For each of the included 73
drugs, 57 2D descriptors were computed by MOE [39]. Also,
51 molecular fragment-count descriptors were computed. In
particular, the used molecular fragments were a subset of the
public 166-bit MACCS key set [59]. SVM classification was
done using the WEKA package [60], and yielded discri-
minant models with an overall percentage of good classi-
fication above 90 %. A similar study based on calculation of
2D and 3D descriptors with MOE and the subsequent
development of SVM models was conducted by Rege et al.
[61] in order to study the interactions of aminoglycoside-
polyamine with DNA.
Another QSAR study was performed to analize the
affinity and selectivity of a novel series of triaryl imidazole
derivatives (see Fig. (2), structure 3) for the glucagon
receptor [62]. The dataset include 30 compounds reported by
Chang et al. [63]. Statistically significant and highly
predictive QSAR models were derived using descriptors
calculated with MOE and employing a computer-assisted
multiple regression procedure performed with the statistical
software SYSTAT [64] and the validation program
VALSTAT [65]. 180 Molecular descriptors were calculated
for the lowest energy conformers of the compounds. The
generated QSAR models revealed that factors related to
hydrophobicity, molecular shape, and geometry predo-
minantly influence the glucagon receptor binding affinity of
the studied triaryl imidazoles, indicating the relevance of
shape specific steric interactions between the molecule and
the receptor.
Another QSAR study has been performed on 5-amino-2-
mercapto-1,3,4-thiadiazole (see Fig. (2), structure 4) based
inhibitors of matrix metalloproteinases (MMPs) and a bac-
terial collagenase known as Clostridium histolyticum colla-
genase (ChC) to understand the structural features influen-
cing the affinity of these inhibitors towards the enzymes
[66]. A large number of 2D descriptors were generated by
means of MOE. Stepwise multiple regression analysis was
used as statistical tool, with the help of the statistical
program VALSTAT [65]. Each obtained QSAR model
explained more than 75% of the total variance (r2 > 0.75).
1.2. Binary QSAR
Binary QSAR is a method for the determination of
quantitative structure activity relationships [67]. The method
accepts binary activity measurements (e.g., pass/fail or
active/inactive) and molecular descriptor vectors as input. A
Bayesian inference technique is used to predict whether or
not a new compound will be active or inactive. A set of 1947
small molecules with molar refractivity data was chosen to
1558 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 Vilar et al.

R1 SO2R1
O

HN N R3
H
N 2
N N O R2

N O Diaryl furanones
N O
N 1
R Pyrazolotriazolopyrimidines
4
O
R2 H
N S
N 3 N SH
H
R3 NH O N
R N
N R1
H
5-amino-2-mercapto-1,3,4-thiadiazole derivatives
Triaryl imidazole derivatives

Fig. (2). Structure of Some Compounds Used for the Calculation of Molecular Descriptors.

test the correctness and robustness of the method in error Binary QSAR analysis are shown in the Table 2. The overall
measurement. Four molecular descriptors calculated with prediction accuracy of these models is very high: 94% for
MOE, were chosen to represent the molecules: two zero’th Binary QSAR model of CA II inhibitors and 89% for the
order and two first order connectivity indices [68]. The best model of ER ligands.
prediction method was implemented using the SVL Table 1. Molecular Descriptors Calculated with MOE by Gao
programming language built into MOE. The results show for Carbonic Anhydrase II Inhibitors and Estrogen
that the method exhibits high accuracy and is robust for error Receptor Ligands
measurement.
Compounds with activities against seven different Table 1. Molecular Descriptors Calculated with MOE
biological targets have been used by Labute [69] to test the
applicability of VSA descriptors for compound discrimi- Symbol Description
nation via Binary QSAR. MOE was used to calculate the
b_ar number of aromatic bonds
SlogP-VSA and SMR-VSA descriptors for each of the
molecules in the database. P_VSA descriptors relate van der b_1rotR fraction of rotatable single bonds
Waals surface area with some atomic property, like logP
(octanol/water) or molar refractivity. A total of seven Binary
0
 zero-order atomic connectivity index
QSAR models were generated and resulted in a high 1
 first-order atomic connectivity index
accuracy of prediction (>95 %) and high significance.
2
 second-order atomic connectivity index
Binary QSAR also was applied to the study of estrogen
receptor ligands [70]. The binding affinities of 463 estrogen 0
v zero-order atomic valence connectivity index
analogues were transformed into a binary data format, and a 1
v first-order atomic valence connectivity index
predictive Binary QSAR model was derived using 410
estrogen analogues as a training set. The model was applied 2
 v
second-order atomic valence connectivity index
to predict the activity of 53 estrogen analogues not included
in the training set. An overall accuracy of 94% was obtained.
1
 Kier first shape index

Another application of Binary QSAR with three-

2
 Kier second shape index
dimensional H-suppressed BCUT metrics (BCUTs) and 3
 Kier third shape index
MOE descriptors (connectivity indices, shape indices, etc)
was performed by Gao using carbonic anhydrase II (CA) 1
 Kier first alpha modified shape index
inhibitors and estrogen receptor (ER) ligands as test case 2
_ Kier second alpha modified shape index
[71]. The calculated MOE descriptors are summarized in
Table 1. The derived Binary QSAR models were validated 3
_ Kier third alpha modified shape index
with two sets of compounds not included in the training sets.

Kier molecular flexibility index
A set of 337 CA II inhibitors (see Fig. (3), structure 1) and a
set of 463 ER ligands were collected from the literature. ASA_H total accessible hydrophobic surface area
DiverseSolutions software [72] was used for the calculation
of BCUT metrics. All other molecular descriptors were logP(o/w) partition coefficient
calculated using MOE. Binary QSAR analysis was carried
out using the MOE Binary QSAR function. Results of
Medicinal Chemistry and the Molecular Operating Environment (MOE)
Table 2. Results of Binary QSAR made by Gao
Comparison of Binary QSAR Models Derived Using Different Sets of Descriptors of CA II Inhibitors
QSAR Model MOE Molecular Descriptors
a
predictive accuracy actives 0.94 (0.92)
inactives 0.72 (0.58)
overall 0.90 (0.86)
Comparison of Binary QSAR Models Derived Using Different Sets of Descriptors of ER Ligands
QSAR Model MOE Molecular Descriptors
predictive accuracy actives 0.58 (0.48)b
inactives 0.91 (0.89)
overall 0.86 (0.83)
a
Value in parentheses is cross-validated accuracy. 337 CA II inhibitors. 287 compounds were chosen as a training set. 50 compounds are inactive and 237 are active in the training
set. b Value in parentheses is the cross-validated accuracy. 400 Estrogen Receptor Ligands compounds were chosen as a training set.
Inhibitors of JNK3 could be useful for treating
Parkinson’s disease, Alzheimer’s disease, epilepsy, stroke,
and other dysfunctions of the central nervous system (CNS)
[73, 74]. Two sets of 2D molecular descriptors (P_VSA and
BCUT) were used to build with MOE Binary QSAR models
of JNK3 ligands (see Fig. (3), structure 2) using different
biological activity thresholds [75]. 32 P_VSA descriptors
were calculated with MOE. These descriptors express
various physicochemical properties (lipophilic, pharma-
cophoric, steric, and electronic) in terms of van der Waals
surface [69] and were reported to be implicitly linked to
ligand binding in other systems. Using the DRAGON
software [76], 64 Burden eigenvalues (BCUT) were compu-
ted and then imported into MOE for the construction of the
models. The best model was found using a 100 nM IC50
threshold with surface-based P_VSA descriptors. This model
had an overall accuracy of 98%. With the same cutoff,
BCUT descriptors led to a lower but still very satisfactory
overall accuracy of 93%. To validate the predictive ability of
the developed models the authors have conducted a leave-
one-out (LOO) analysis. For the models built using P_VSA
descriptors, the LOO cross-validated overall accuracy range
from 90% to 94%.
1.3. Principal Component Analysis (PCA)
Principal Component Analysis (PCA) is a statistical
technique of synthesis of the information, or reduction of the
dimension (number of variables). When we have too many
variables to analyze, the objective will be to reduce them to a
smaller number losing the smallest possible quantity of
information. The principal components or factors will be a
lineal combination of the original variables, and they will
also be independent of each other [77, 78].
An algorithm based on PCA was investigated by Xue et
al. [79] to classify molecules in a database consisting of 455
compounds with activities against seven different biological
targets. The compounds were collected from the literature
and included inhibitors of CAII, cyclooxygenase-2 (Cox-2),
Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1559
BCUT Metrics Combination of Descriptors
0.93 (0.89) 0.94 (0.91)
0.94 (0.92) 0.94 (0.92)
0.93 (0.89) 0.94 (0.91)
BCUT Metrics Combination of Descriptors
0.78 (0.67) 0.80 (0.73)
0.85 (0.84) 0.90 (0.90)
0.84 (0.81) 0.89 (0.88)
HIV-1 protease, and tyrosine kinases, and ligands for the
benzodiazepine 5-HT receptors, and histamine H3. A set of
57 SSKey-type descriptors, containing 41 of 166 MDL
structural keys, which represent small molecular fragments,
have been calculated. Other 16 molecular descriptors
implemented in MOE were investigated. In particular, the
MOE descriptors were related to bulkiness (e.g., molecular
refractivity) or to 2D properties (e.g., connectivity index).
Complete factorial analysis, i.e. evaluation of all possible
combinations of the 17 molecular descriptors, was performed
by means of a PCA-based compound classification [80] with
the QuaSAR-Cluster function of MOE [39]. The approach
has been discussed in detail elsewhere (see URL:
http://www.chemcomp.com/article/cluster.htm). With the
MOE QuaSAR-Cluster calculations, the authors found that
three principal components and eight intervals for signature
coding were sufficient for effective compound classification.
1.4. Partial Least Squares (PLS)
Partial Least Squares (PLS) is a technique that reduces
dimensionality in a regression context using orthogonal
components. PLS combines characteristic of PCA and MLR
[81, 82].
French et al. [83] developed a QSAR Model for Inhi-
bition of N-Myristoyltransferase (hNMT-1) by cyclohexyl-
octahydropyrrolo[1,2-a]pyrazine (COPPs). MOE was used to
calculate a large number of 2D chemical descriptors for each
of the COPP compounds (see Fig. (4), structure 1) which
were applied for the generation of predictive equations by
means of PLS analyses. The process resulted in an optimized
QSAR equation with 37 descriptors and the following
statistical parameters: root mean square error, 0.50;
correlation coefficient (r2), 0.72; cross-validated root mean
square error, 1.02; cross-validated r2, 0.18. The descriptors
making the largest contributions to the equation included:
zagreb (an index describing the molecular connectivity and
shape of the heavy atoms in the molecule); weight (the
molecular weight of the compound); vsa_hyd (a
1560 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18
Representative structures
sulfonamides N N
H3CCOHN SO2NEt2
S
H3CCOHN SO2NHOH
N
SO2NH2
H3CH2CO S
N CH2NH
SO2
Data Profile of CA II Inhibitors
N NH
O N
Fig. (3). Compounds Used in Binary QSAR Studies.
pharmacophore feature that approximates the sum of Van der
Waal surface areas of hydrophobic atoms); and WeinerPath
and WeinerPol (adjacency and distance matrix descriptors
for path and polarity, respectively). These descriptors
indicate that specific aspects of molecular size, shape, and
polarity are critical determinants for inhibition of NMT.
1.5. Multiple Linear Regression (MLR)
Multiple Linear Regression (MLR) can be used in the
prediction of values of the dependent variable based on a
combination of independent variables [84-86]. MLR analysis
is based on the hypothesis that the dependent variable (in our
case the biological activity) has a lineal relationship with the
independent variables (molecular descriptors).
Yuan and Parrill studied a number of diverse inhibitors of
the HIV-1 integrase [87], which is recognized as an
important target for therapeutic development against AIDS.
QSAR models were constructed to predict the IC50 values for
two structural classes of molecules (salicyhydrazines and
tyrphostins; see Fig. (4), structure 2). QSAR studies were
performed with MOE and Cerius2 [88]. Using MLR [30], the
best linear model obtained for the description of the biolo-
gical activity of the salicylhydrazines, with an R2 of 0.93,
was:
log(1/IC50 ) = 18.63 - 0.142
vdw_area - 0.0792
PEOE_VSA_NEG +
0.478
(log P) 2 + 0.125
KierA1 + 2.133
Kier1
Vilar et al.
amides OCH2CH(OH)CH2OCONH2
OMe
alcohols and phenols OH
benzoic acid COOH
amine
1
NH
N
N
H
N
2 S
Some JNK3 ligands
The best linear model to describe the biological activity
of the tyrphostins, with an R2 of 0.77, was:
log(1/IC50 ) = 4.220 + 0.0102
vdw_area - 0.0092
PEOE_VSA_NEG +
0.0643
(log P) 2 - 0.199
KierA1 + 0.0456
Kier1 (4)
In both equations (log P)2 is the squared log of the
octanol/water partition coefficient; vdw_area is the area of
van der Waals surface; PEOE_VSA_NEG is the sum of the
van der Waals surface area of atoms whose partial charges
are negative; Kier1 and KierA1 are the Kier Kappa Shape
Indices, which compare the molecular graph with minimal
and maximal molecular graphs and reflect different aspects
of molecular shape [53]. In particular, Kier1 reflects the
number of heavy atoms and the degree of unsaturation in the
molecule, while KierA1 includes influences from atomic
identity, thus reflecting heteroatom content, in addition to the
number of heavy atoms and degree of unsaturation.
The same authors reported the development of other
QSAR models for HIV-1 integrase inhibition [89]. The best
QSAR model derived for a set of 11 structural classes of
molecules had a correlation coefficient (r2) of only 0.54 and
a cross-validated correlation coefficient (q2) of only 0.42.
This indicated that the compounds studied may differ in the
exact relationship between structure and inhibition, perhaps
(3) through interactions with different subsets of amino acids in
the binding pocket, or due to the presence of non-
Medicinal Chemistry and the Molecular Operating Environment (MOE) Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1561

OH O
R H
N
N
H
O OH
HO OH
OH O O
2
N N Cl
H
R
1
R NC
N R
N R
HO OH
COPPs compounds Some salicylhydrazines and tyrphostins studied

R R R R

X
X X
X R 3
R

R R

R
COX-2 inhibitors

Fig. (4). Compounds Studied in Different Statistical Analysis with MOE.

overlapping binding pockets. Descriptor-based cluster
analysis indicated that the 11 structural classes of integrase
inhibitors studied belonged to two clusters, one consisting of
five structural classes (tyrphostins, coumarins, sulfonamides,
chicoric acids, and tetracyclines), and the other of six
structural classes (arylamides and naphthalene-based com-
pounds, thiazolothiazepines, curcumins, salicylhydrazines,
styrylquinolines, depsides, and depsidones). QSAR models
for these two clusters had r2 values of 0.79 and 0.82 and q2
values of 0.71 and 0.74, respectively. MOE was used to
calculate over 180 descriptors. All QSAR studies were
performed with MOE and Cerius2.
An MLR analysis of P2Y11 receptor antagonists was
performed by Ullmann et al. [90] Fragment constant
descriptors of physicochemical properties were derived with
BuildQSAR [91], while the subsequent MLR analysis was
conducted with MOE. The analysis yielded the following
three equations for the pKi calculation:
p
i = 7.282 - 2.100R - 0.410B5 (5) r2 = 0.880. RMSE
= 0.182
2 QSAR, and a classification technique based upon a Decision
pKi = - 46.066 - 0.443B5 - 106.376Q(Oortho) (6) r = 0.851.
RMSE = 0.328
pKi = - 22.65 - 1.352R - 0.426B5 - 59.535Q(Oortho) (7 ) r2 =
0.946. RMSE = 0.122
Where R is the resonance, B5 is the size and Q(Oortho)
is the partial charge of the ortho oxygen.
1.6. Combination of Different Statistical Analysis
Using classification (Self-Organizing Map, Learning
Vector Quantization, Binary QSAR, Decision Tree) and
regression algorithms (Partial Least Square, Bayesian
Regularized Artificial Neural Network, Genetic Algorithm
coupled to k Nearest Neighbors, Regression Linear), Baurin
et al. [92] reported the generation of eight 2D-QSAR models
for a 266 COX-2 inhibitor training set (see Fig. (4), structure
3). The predictive performances of these eight models were
subsequently compared using a test set of 88 COX-2
inhibitors with good results. Each ligand was described by
52 2D descriptors expressed as van der Waals Surface Areas
(P_VSA) calculated with MOE [39, 69] and its COX-2
binding IC50.
Of the different QSAR models, three models were built
with MOE and were based on a linear regression, Binary
Tree algorithm, also called Recursive Partitioning (RP) [93].
The results of classification models are shown in the Fig. (5).
1562 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18
Fig. (5). Classification of the Predictions Made by the Four Quantitative COX-2 Models and the Four Qualitative COX-2 Models on the 266
Ligand Training Set (True Positive, False Negative, True Negative, False Positive; Compounds Number; Percentage).
Subsequently, the authors generated a QSAR consensus
prediction protocol that resulted to be more predictive than
any single QSAR model.
Costanzi et al. [94] combined QSAR and Docking scores
in a ligand- and structure-based consensus model (LIST-CM)
for the prediction of the activity of a series of P2Y1
antagonists. This model was based on LiaScore (Glide
scoring function) [95], SGB-LIE [96], CoMFA [97],
CoMSIA [98], MOE QSAR with 2D descriptors, MOE
QSAR with 3D descriptors, and MOE QSAR with 2D and
3D descriptors [39]. The consensus model yielded a
prediction power superior to that of any individual model.
2. MOLECULAR DOCKING WITH MOE
MOE-Dock searches favorable binding configurations
between ligands and macromolecular targets. The search is
carried out inside a 3D docking box. The box size and
orientation depends on the selected atoms. The search is
carried out by means of molecular mechanics forcefields [99,
100] and it is possible to use two different protocols that
optimize the spatial contacts and the electrostatic interactions
among the molecules generating random changes to the
coordinates of the ligands. The two different protocols
available are simulated annealing and tabu search [101].
These methods have an acceptance-rejection test for each
Vilar et al.
molecular move to find an optimal solution. Molecular
moves that decrease the energy of the system are accepted,
while moves that increase the energy can be accepted or not.
Simulated annealing is based on the Monte Carlo method
[25]. The following parameters control the search: cycles per
run (each run consists of different cycles and each cycle
consists of a various steps or moves), iteration limit, and
initial temperature.
Tabu search performs a stochastic search maintaining a
list of previously visited conformations that are forbidden to
future moves. This is very useful to drive the search into
unvisited areas of space. The new conformations are
compared to the visited conformations using the root mean
square (RMS) deviation. The parameters that control the
search process are the steps per run, moves per step, and tabu
list length.
Docking run begins with a random conformation of the
ligand or a user-determined conformation. In the context of a
binding configuration search, a move consists of random
perturbations of some or all of the rotatable bonds of the
ligand. It is also possible to restrict the search using angle,
torsion, and distance constraints. The interaction energies
between the ligand and the target are calculated with the
built-in potential function or grid-based potential fields. In
Medicinal Chemistry and the Molecular Operating Environment (MOE)
the grid-based method, the interaction energy is calculated
using electrostatic and van der Waals potential fields that
have been sampled on a grid overlaying the docking box.
The grid-based method calculates the potential energy grids
only at the beginning of the docking calculation. This
method is faster than the built-in potential energy function.
Finally, MOE-Dock saves the resulting conformations
and energies (total energy, the electrostatic energy, the van
der Waal energy between the protein and the ligand, the
energy of the ligand and the salvation energy) into a MOE
database.
The software MOE has been used in various studies to
carry out molecular docking of different ligands to a number
of biological targets. In this section, we review a series of
studies performed for various therapeutic targets, which
demonstrate the applicability of the MOE software to
structure-based computational medicinal chemistry.
It is worth noting that the results in this type of studies
vary according to the crystallographic information available
for different proteins and protein-ligand complexes. When
the docking protocol is adjusted through the crystallized
structures the results are more accurate and reliable it is more
remarkable. When the docking experiments are conducted at
homology models, the results should be interpreted with
more caution due to the lack of an experimental model.
2.1. Carbonic Anhydrases (CA)
Esposito et al. [102] reported the docking of
sulfonamides to CA II and IV, which are of interest due to
their application in glaucoma therapy [103]. The study was
carried out with the use of MOE-Dock and was based on the
X-ray structures of the CA II complex with the inhibitors
AMS and AZP, and of the CA IV complex with AZP. In the
majority of the cases, the structure with the lowest or next
lowest calculated interaction energy was the overall best-
docked structure. Using this protocol the authors predicted
Known CK2 Inhibitors
(15 compounds)
Conformational Space Exploration
(performed by OMEGA)
Rigid-body shape fitting
(performed by FRED)
Hit selection
Fig. (6). Flowchart of the High-throughput Consensus Docking Made by Cozza et al. and the Structure of Ellagic Acid.
Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1563
the correct orientation and the qualitative affinity of the
substrates for a specific isozyme.
2.2. Protein Kinases
Anthracycline antibiotics are among the most effective
agents used for the treatment of cancer [104]. Roaten et al.
conducted a molecular modeling study to investigate the
interaction of the anthracycline AD 198 with the Protein
Kinase C-
[105]. The structure of AD 198 was generated
using the "Small Molecule Builder" application of MOE and
minimized using the AMBER94 force field [106].
Conformers of AD 198 were generated using the random
incremental pulse search (RIPS) methodology within MOE.
Docking of AD 198 was carried out manually or using the
automated docking module MOE-DOCK. The automatic
docking procedure was validated by removing phorbol-13-
acetate from the crystallographic complex and docking it
back in. The study yielded three models of AD 198 bound
into the groove formed between amino acid residues 6-13
and 21-27 of the
C1b domain in a manner similar to that
reported for phorbol-13-acetate and other ligands of the C1
domain. Two of the identified models were consistent with
previous experimental data demonstrating the importance of
the 14-valerate side chain of AD 198 in binding to the C1
domain. These studies are a starting point for the rational
design of potential new drugs targeting PKC and other
proteins with C1 domains.
Using a virtual screening approach, Cozza et al. [107]
identified the ellagic acid, a naturally occurring tannic acid
derivative, as a novel potent Casein Kinase 2 inhibitor (CK2
inhibitor). At present, ellagic acid represents the most potent
known CK2 inhibitor (Ki = 20 nM). In particular, a
combination of four docking protocols (MOE-Dock [39],
Glide [95], Fred [108], and Gold [109]) and five scoring
functions (MOE-Score [39], GlideScore [95], GoldScore
[109], ChemScore [109], and Xscore [110] was utilized to
appropriately dock and rank the large studied database. The
MMS-Database
(2000 NP-compounds)
OH
O O OH
HO O O
OH
Ellagic acid
Top 50 %
Flexible complementarity
(by MOE-Dock/Glide/Gold)
Top 5 %
Consensus scoring
(by MOE-Dock/Glide/Gold/Xscore)
1564 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 Vilar et al.

flowchart of the high-throughput consensus docking and the
structure of ellagic acid are shown in the Fig. (6).
Tetrabromocinnamic acid (TBCA, see Fig. (7), structure
1) and related compounds represent another class of specific
Protein Kinase CK2 inhibitors (TBCA IC50 = 0.11 μM).
These compounds were docked at the human CK2 (PDB ID:
1JWH) [111] by Pagano et al. [112]. The structures of all
ATP-competitive inhibitors were constructed with MOE and
minimized, and subsequently docked at the CK2 by means of
MOE-Dock and GOLD [109]. Only the top-ranked pose of
each ligand obtained by both docking protocols was
evaluated. MOE conformational samplings were conducted
within a user-specified 3D docking box. From modeling it
also appears that the brominated benzene ring of TBCA is
more remote from the side chains of V66 and I164 than it is
in the case of the most widely employed inhibitor 4,5,6,7-
tetrabromobenzotriazole (TBB).
2.3. Topoisomerase II
Moro et al. [113] studied clerocidin (CL, see Fig. (7),
structure 2), a diterpenoid with antibacterial and antitumor
activity [114]. This compound stimulates in vitro DNA
cleavage mediated by mammalian and bacterial Topo-
isomerase (Topo) II [115]. CL was docked into both the
major and minor grooves of DNA using MOE-Dock. The
authors demonstrate that trapping of topoisomerases by CL is
specific for type II enzymes. The guanine-alkylating ability
of CL suggests an unprecedented mechanism of Topo II
poisoning, according to which the enzyme renders the drug
reactive toward DNA by distorting the double-helical
structure of the nucleic acid at the cleavage site. Moro et al.
[116] have also performed molecular modeling studies to
construct an interaction model for anthracycline activity
against DNA Topo II. Their findings may explain several
established structure-activity relationships of antitumor
anthracyclines and may thus provide a framework for the
development of effective Topo II poisons.
2.4. HIV-1 Reverse Transcriptase
The interactions of non-nucleoside inhibitors of HIV-1
Reverse Transcriptase with the non-nucleoside binding
pocket of the enzyme are of great pharmaceutical interest
[117-120]. Zhou et al. [121] docked known and potential
non-nucleoside reverse transcriptase inhibitors (potam-
getonin, neotripterifordin, tripterifordin, kaurenoic acid,
kaurane) at the enzyme by means of MOE-Dock. The
coordinates of nevirapine and 105U91 were obtained from
X-ray structures (PDB codes 1VRT, 3HVT and 1RTH). The
original crystal structures of 3HVT, 1VRT, and 1RTH [122]
were used to validate the applicability of MOE-Dock to the
HIV-1 RT system by moving the inhibitor outside of active

O
Br O 3 R1
Br HN X
OH
N
N N
Br 1
N O
Br N
Tetrabromocinnamic acid (TBCA) Pyrazolotriazolopyrimidines
N
OH R O
15 O O
14 HO
O
13 O O

H H

3
4
2
O O
Structure of clerocidin (CL). The dicarbonylic form of the drug (left) is shown in equilibrium with the closed hemi-acetalic ring (right). The numbered
atoms outline electrophilic carbons possibly involved in the reaction with nucleophilic moieties in the DNA.

O NHR1
R
HN N
N
N
R N R N R
N
N
O 4 5
Pyrazoloquinolines
1,2,4-Triazolo[4,3-a]quinoxaline Derivatives

Fig. (7). Structure of Some Compounds Studied with Docking.

Medicinal Chemistry and the Molecular Operating Environment (MOE)
site entrance and then docking it back into the active site.
The docking results of the five diterpenoids showed that the
structurally homologous inhibitors bind with a very similar
position and orientation within the HIV-1 RT.
2.5. Helicobacter Pylori Urease
A homology model of the Helicobacter pylori urease was
developed by using the crystal structure of the urease from
Klebsiella aerogenes as template (entry 2KAU [123]). The
protein modeling tools available in the computer software
package MOE were used for protein modeling. The
geometrically optimized protein structure was used as a
starting point for docking experiments. Acetohydroxamic
acid was docked into the active pocket of the protein [124]
by means of MOE-Dock [39]. Specific information
identifying the amino acids involved in the formation of the
urease active pocket was obtained from the literature, and
this information was used to define the docking box and
volume to be explored during docking [125]. Twenty-five
putative complex geometries were generated and optimized
during the docking process. However, the final configuration
was selected on the basis of similarity to the crystal structure
of acetohydroxamic acid as bound to the K. aerogenes urease
[126]. In both cases, the hydroxamic acid binds to the nickel
ion, which is present in the active site and is very
fundamental for the activity of the enzyme [125].
2.6. Human Adenosine Receptors
Baraldi et al. performed a molecular modeling inves-
tigation intended to elucidate the binding mode of new
human A3 adenosine receptor antagonists and, in particular,
to better rationalize the correlation between their chemical
structures and the corresponding binding results [127]. By
homology modeling, the authors have built an improved
model of the transmembrane region of the human A3
receptor, using the crystal structure of rhodopsin as template
[128]. The human A3 receptor model was built and
optimized using MOE. All pyrazolo[4,3-e]-1,2,4-triazolo
[1,5-c]pyrimidine derivatives (see Fig. (7), structure 3) were
fully optimized using RHF/AM1 semiempirical calculations
[129]. The software package Gaussian98 was utilized for all
quantum mechanical calculations [130]. The ligands were
docked into the binding site by using MOE-Dock (see Fig.
(8)). The study provided useful information concerning the
optimal structural requirements necessary for antagonist
recognition by the A3 adenosine receptor. By the use of
molecular modeling studies, it has been demonstrated that
the steric characteristics of the substituent at the para
position on the phenyl ring play a fundamental role for
affinity at the human A3 receptors. Moro et al. [131] investi-
gated by means of MOE optimal structural requirements
necessary for molecular recognition of pyrazolotriazolopyri-
midines as antagonists of the human A2B adenosine receptor.
The studied demonstrated that bulky groups at the N5 and
N8 positions on the core of the molecules confer a slightly
better affinity for the A2B adenosine receptor subtype with
respect to the other receptor subtypes, and clarified the
differences in the interaction of this class of compounds with
the human A2B and A3 receptors. More recently, new series
of 5-Heteroarylcarbamoylaminopyrazolo[4,3-e]1,2,4-triazolo
[1,5-c]pyrimidines as human A3 adenosine receptor anta-
gonists were also studied [132].
Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1565
With a similar molecular modeling approach a study was
carried out to elucidate the binding mode of triazolo-
quinoxalines (see Fig. (7), structure 4) as new selective
human A3 adenosine receptor antagonists [133-135].
Fig. (8). Side View of the A3-inhibitor Complex Model.
Another paper reports the study of some 2-aryl-
pyrazolo[3,4-c]quinolin-4-ones, 4-amines, and 4-amino-
substituted derivatives (see Fig. (7), structure 5) designed as
antagonists of the human A3 receptor [136], towards which
some of the compounds showed a nanomolar affinity.
Homology modeling, energy calculation, and docking
studies were performed using MOE. All docked structures
were fully optimized without geometry constraints using
RHF/AM1 semiempirical calculations. A flow chart of the
applied ligand-based homology modeling technique is shown
in the Fig. (9). Molecular modeling studies were performed
on the pyrazoloquinoline derivatives in order to identify the
hypothetical binding motif of this class of compounds and
rationalize the observed SAR. The main issues to be
addressed were to clarify the different role of the R subs-
tituent on the affinity and selectivity for the human A3
receptor of the 4-oxo/4-amino and 4-acylamino/4-benzyl-
ureido derivatives and to interpret the advantageous effect of
the 4-acylamino moieties. The effect of a hydrophobic R
substituent appeared to be significantly different for the two
classes of compounds. The 4-oxo and 4-amino derivatives
interacted only with the upper part of the binding pocket, and
the introduction of a methyl group in meta or para position of
the phenyl ring increased affinity versus the human A3
receptor. However, molecular docking studies carried out for
all the pyrazoloquinoline antagonists, using the appropriate
conformational states of the receptor, have shown a similar
binding motif, indicating that a common receptor-driven
pharmacophore model can be depicted. An important
hydrogen-bonding network could be observed in all
energetically stable docked conformations of all pyrazolo-
quinoline antagonists; in particular, Thr94, His95, and
Ser247 were able to interact through hydrogen bonding with
1566 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18
Fig. (9). Flow Chart of the Ligand-based Homology Modeling Technique Used to Study Pyrazoloquinoline Antagonists.
the studied compounds. Finally, the pyrazoloquinoline
moiety did not present any specific hydrogen-bonding
interaction with Gln167, Phe168, or Asn250 as previously
reported for other classes of antagonists.
2.7. NAD(P)H/Quinone Acceptor Oxidoreductase Type 1
(QR1)
NAD(P)H/quinone acceptor oxidoreductase type 1 (QR1)
protects cells from cytotoxic and neoplastic effects of
quinones through two-electron reduction [137]. Docking,
and binding affinity calculations were performed on a series
of structurally varied quinone substrates [138]. MOE was
used to perform molecular building, coordinate preparation,
docking, and calculations of solvation energies and relative
binding free energies. Autodock3 [139] also was used for
docking and relative binding free energy calculations. A
good correlation between calculated and measured binding
affinities was obtained. Also in this case, to validate the
MOE-dock method, the authors docked duroquinone back
into the active site. The experimental and theoretical studies
independently supported a model in which quinones (with
one to three fused aromatic rings) bind in the QR1 active site
utilizing a -stacking interaction with the isoalloxazine ring
of the FAD cofactor. In the QR1 active site, the duroquinone
ring stacks 3.5 Å above the flavin ring, with carbonyl
oxygens running almost parallel with the length of the
isoalloxazine ring. One quinoid carbonyl forms a hydrogen
bond with a water molecule, which in turn hydrogen bonds
to Y128 and H161. The other carbonyl hydrogen bonds to
Y126.
2.8. Cyclooxygenase
A molecular-docking study was carried out to explore the
steric and electrostatic complementarities of novel com-
Vilar et al.
pounds within the cyclooxygenase COX-1 and COX-2
binding cavities [140]. The ground-state geometry of all
docked structures were fully optimized using RHF/3-21G*
ab initio calculations. The Spartan software package was
utilized for all quantum-mechanical calculations [141]. The
X-ray crystal structure of COX-1 complexed with ‘
-methyl-
4-biphenylacetic acid’ (PDB entry 1Q4G) [111], and that of
COX-2 complexed with the selective inhibitor SC-558 (1b;
PDB entry 1CX2) [111] were used to perform docking
studies. All furoxan derivatives (see Fig. (10), structure 1)
were docked into the recognition cavity using MOE-Dock.
Some compounds showed good steric and electrostatic
complementary with the COX-2 cavity. For COX-1 it is
different and none of the products exhibited any significant
complementary. Several authors reported certain structural
differences between COX-1 and COX-2 [142]. Ile523 in
COX-1 is substituted by Val523 in COX-2 and it permits
access to a side pocket adjacent to the central COX channel.
The enzyme COX-2 has an Arg513 and not and Hist513 like
in COX-1. This substitution permits to the inhibitors have an
H-bonding with the SO2 moiety of COX-2 The substitution
of His513 in COX-1 by Arg513 in COX-2 allows for H-
bonding with the SO2 moiety of COX-2 inhibitors. There is
another difference because the enzyme COX-1 has a Phe503
and COX-2 has a Leu503. This allows larger inhibitors to
bind in the cavity of the enzyme.
Furthermore, the orientation of the highly potent and
selective COX-2 inhibitors (3-alkylthio-4,5-diaryl-4H-1,2,4-
triazoles) [143] in the COX-2 active site was examined with
MOE. The ligand molecules were constructed using the
Builder module and were energy optimized. Docking at
COX-2 (1cx2) was conducted within a specified 3D docking
box with MOE-Dock using simulated annealing based on the
Medicinal Chemistry and the Molecular Operating Environment (MOE) Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18 1567

Monte Carlo method and MMFF94 molecular mechanics (HCVP), polypeptide deformylase (PDF), and peroxisome
force fields. Molecular modeling studies indicated that the proliferator-activated receptor
(PPAR
). The goal of this
SO2Me moiety inserts deeply into the COX-2 secondary study was to examine three tasks: binding mode prediction,
pocket andthe C-3 SR sulfur atom forms a weak hydrogen virtual screening for lead identification, and rank-ordering by
bond with NH2 atom of Arg120. affinity for lead optimization. Some programs evaluated
have different scoring functions or docking algorithms to
2.9. G-Quadruplex of Human Telomere DNA resulting in a total of 19 docking protocols (see Table 3).
A novel series of benzothiazole urea and thiourea Table 3. Docking Softwares and Protocols Included in the
derivatives was synthesized and evaluated for its in vitro Docking Study Made by Warren et al.
cytotoxicity against MCF-7 breast cancer cells [144]. The
compound N1-(benzothiazol-2-yl)-N3-morpholinourea
displayed the highest cytotoxic activity in this series. A Docking Software Protocols
docked pose of this compound was obtained bound to G- MOE
quadruplex of human telomere DNA active site. The
coordinates of the X-ray crystal structure of I (see Fig. (10), MVP
structure 2) bound to the G-quadruplex were obtained from
Dock4 Chemistry
Protein Data Bank (PDBID: 1L1H). The ligand molecules
were constructed using the builder module and were energy Contact
minimized. The active site of G-quadruplex was identified
using the MOE-Alpha Site Finder, and then ligands were Energy
docked within this active site using the MOE-Dock. The Fred ChemScore
lowest energy conformation was selected and the ligand
interactions (hydrogen bonding and hydrophobic interaction) ScreenScore
with G-quadruplex were determined. Docking of the energy DockIt
minimized conformation of the compound II (the most
effective; see Fig. (10), structure 3) into the G-quadruplex of Glide
human telomere DNA showed a very close pattern of
Gold
binding to the G-quadruplex of human telomere DNA as that
resulting from the crystal structure of I. In both cases (I and FlexX FlexX score
II) a hydrogen bond interaction could be observed between a
carbonyl group of the ligand and the thiamine 1006 base. DrugScore

LigFit CVFF
R
Dreiding
1 O O
S Flo Mcdock
N
N N Mcdock+
N H H
N N
Fulldock
O 3
General scaffold of furoxan Compound II Sdock
derivatives studied by Moro et al.
Zdock

N N

O 2 O The first goal was the prediction of protein-bound

HN N NH
Compound I
Fig. (10). Structure of Some Compounds Studied with Docking.
2.10. Inaccuracy of Scoring Functions in Different
Targets
An evaluation of 10 docking programs (among them the
MOE) and different scoring functions was conducted by
Warren et al. [145] against eight proteins of seven protein
types: chk1 kinase, factor Xa, gyrase, methionyl tRNA
synthetase (MRS), hepatitis C RNA polymerase NS5B
conformations. Different docking protocols were used to
predict bound conformations for the 136 compounds for
which protein/ligand crystal structures exist. The docking
programs were able to reproduce the conformations of the
crystals. For all proteins except HCVP, at least one program
was able to dock 40% of the ligands within 2 Å of the crystal
conformation. For several protein targets, 90% of the ligands
could be docked in the correct orientation. The docking
algorithms effectively explored the conformational space to
generate correct docked poses. A limitation was that the
scoring functions were less successful at distinguishing the
pose closest to the crystal conformation. In general, when
considering only the best-scoring pose, only some com-
pounds were docked within 2 or 4 Å of the crystallographic
conformation. Another limitation was that no single docking
program performed well across all protein targets. In others
1568 Current Topics in Medicinal Chemistry, 2008, Vol. 8, No. 18
words, there is no one program that is located near the top of
the list.
The second interesting aspect was to know if scoring
functions could distinguish active chemotypes from inactive
chemotypes. With the application of knowledge about the
protein target, docking algorithms and their scoring functions
could carry out a virtual screening and identify leads, and
combining the results of the different docking programs, it
was possible to identify active compounds from a pool of
decoy compounds.
Another goal of this molecular docking study was to
quantify the relationship between docking scores and
compound affinity. In the studied cases no statistically
significant relationship existed between docking scores and
ligand affinity. The authors have also demonstrated that there
was no consistent improvement in the correlation between
scoring functions and experimental affinity when only
docked poses similar to the crystallographic data were taken
into account.
CONCLUSIONS
The increased complexity of the techniques that use
computers for the acquisition and analysis of data caused a
rapid expansion of the field of Bioinformatics. With the
development of computer science and with the introduction
of the use of computers in pharmacology, chemistry, and
biology, a series of methodologies like QSAR and molecular
Docking, have been developed. These methodologies found
have been largely applied in Medicinal Chemistry for the
discovery and rational design of drugs, and for the
explanation of many chemical and biological processes. In
silico methodologies have been applied to many studies to
rationalize the structure-activity relationship between
inhibitors and biological targets.
However, it is necessary to highlight that the quality of
the theoretical models developed through this type of
methodologies greatly depends on the available experimental
information. If extensive experimental information is
available, then it is possible to develop meaningful and
robust models. If not, the inaccuracy typical of homology
model may significantly affect the reliability of the results. It
is also convenient to emphasize that the predictions made
with these techniques should be based on a training of the
model. In particular, these methods should be applied with
great caution when the compounds that we want to model are
significantly different from the compounds included in the
training set. It is also important to highlight that this type of
methodologies have a series of limitations, as the lack of
correlation between the scoring function and the experi-
mental activity. Despite the inaccuracy of scoring functions,
docking programs are able to reproduce experimentally
observed binding modes and in many cases identify the
correct target-ligand conformation.
For these reasons and despite the great utility of these
methodologies it is necessary to continue working to perfect
the existent techniques and to search new methods that allow
a more precise prediction of the biological properties.
Vilar et al.
ACKNOWLEDGMENTS
The authors acknowledge scholarship funding from the
Xunta de Galicia for one-year post-doctoral position (2007)
in the Molecular Modeling Section, Dipartimento di Scienze
Farmaceutiche, University of Padova, Italy. Thanks are also
given to Dr. Humberto González-Díaz. S. Vilar acknow-
ledges to Dr. Stefano Costanzi his collaboration and his
important help to improve the manuscript.
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