Journal of Molecular Structure 1224 (2021) 129006

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Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Computational identification of potential dipeptidyl peptidase (DPP)-IV

inhibitors: Structure based virtual screening, molecular dynamics
simulation and knowledge based SAR studies
Virendra Nath a, Manish Ramchandani a, Neeraj Kumar b, Rohini Agrawal c, Vipin Kumar a,∗
a
Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Ajmer-301817, India
b
Bhupal Nobles’ College of Pharmacy, Bhupal Nobles’University, Udaipur-313001, India
c
College of Pharmacy, JSS Academy of Technical Sciences, Noida, Uttar Pradesh

a r t i c l e i n f o a b s t r a c t

Article history: Type 2 Diabetes mellitus (T2DM) is a globally leading metabolic problem with increased morbidity and
Received 6 May 2020 mortality. Current medication therapies in the market to control diabetes are not sufficient and there-
Revised 13 July 2020
fore, there is further need to develop more selective and effective treatment approaches. Inhibition of
Accepted 31 July 2020
Dipeptidyl-peptidase-IV (DPP-IV) enzyme may serve as an interesting target for developing novel anti-
Available online 31 July 2020
diabetic drug candidate. In the present study, hierarchical virtual screening of drug like compounds was
Keywords: done followed by molecular dynamics simulation and knowledge-based structure-activity relation (SAR)
Binding energy study in order to retrieve hit compound as prospective inhibitors of DPP-IV enzyme. Important amino
Diabetes mellitus acid residues present in the active target site were acknowledged as vital and were also found to have
Docking similar interactions with the potential hits. Further, in silico technique was undertaken to identify ubiq-
DPP-IV uitous promising hits against DPP-IV enzyme and this was followed by calculation of binding energy
MD simulation
and absorption, distribution, metabolism, excretion (ADME) prediction that could possibly support their
SAR
pharmacokinetic prospective. Furthermore, stability study using molecular dynamics simulation of protein
complex was accomplished with the most capable targeted hit established in the present study. In the
end, comparative analysis of 3-dimensional binding pose, orientation and planar structure of the potential
retrieved hit was done with marketed drugs (alogliptin and sitagliptin) in order to develop knowledge-
based structure-activity relationship, which proved the successful designing of DPP-IV enzyme inhibitors.
© 2020 Published by Elsevier B.V.

1. Introduction
Type2 diabetes mellitus is a worldwide rising public health con-
cern. In U.S., more than 23 million people have a medically de-
clared diabetes [1]. The World Health Organization (WHO) esti-
mates the number of people with diabetes to be approximately
180 million. This number is projected to double by 2030. Type 2
diabetes mellitus (T2DM) is a progressive disease characterized by
high levels of glucose resulting from insulin resistance and im-
pairment of insulin secretion [2]. Many of the proteins and en-
Abbreviations: ADME, Absorption Distribution Metabolism Excretion; HTVS,
High throughput virtual screening; MD, Molecular dynamics; MMGBSA, Molecu-
lar mechanics generalized born solvation accessible; PDB, Protein data bank; DPP,
Dipetidyl peptidase; RMSD, Root mean square deviation; RMSF, Root mean square
fluctuation; SAR, Structural activity relationship; SP, Simple Precision; T2DM, TypeII
Diabetes mellitus; XP, Extra precision.
∗
Corresponding author at: Department of Pharmaceutical Sciences, Central Uni-
versity of Haryana, Mahendergarh-123031, India.
E-mail address: vipbhardwaj@rediffmail.com (V. Kumar).
zymes serve as their targets and the associated drug therapies
involved in Type2 DM involve Gulcagon like peptide (GLP-1), G-
Protein couple receptor40 (GPR40), G-Protein couple receptor120
(GPR120), Sodium glucose transport-2 (SGLT-2), Peroxisome pro-
liferator activated receptor-gamma (PPARγ ), etc. [3–7]. Among all
the targets associated in the mechanistic class for treatment of
T2DM, Dipeptidyl-peptidase-4 (DPP-4) is a widely distributed ser-
ine protease that is involved in glucose metabolism and is present
in solubilized form in blood or anchored into tissue membranes
and has also been proven as a validated target for antidiabetic
therapy recently. Further, inhibition of DPP-4 has been shown to
indirectly stimulate the secretion of insulin. The mechanism of
anti-diabetic therapy is probably through increased incretin (GLP-
1 and GIP) release after the food intake, thus inhibiting release of
glucagon, which stimulates insulin secretion and thereby decreases
blood glucose levels [8,9]. Presently, some of the DPP-IV inhibitors
are available worldwide such as; sitagliptin, vildagliptin, alogliptin,
linagliptin, teneligliptin, anagliptin, saxagliptin [10,11]. These sub-
strates are of different nature, in which alogliptin, tenegliptin,

https://doi.org/10.1016/j.molstruc.2020.129006
0022-2860/© 2020 Published by Elsevier B.V.
2 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006

Fig. 1. Overview of methodology in flow diagram.

sitagliptin, linagliptin are non-covalent, while saxagliptin and

vildagliptin are the covalent type of DPP-IV inhibitors [12]. Several
drugs having different chemical scaffolds were reported in litera-
ture against various diseases such as; quinoline are active as anti-
amoebic, antiviral, anti-parasitic, anti-microbial, anticancer, etc.
Oxadiazole acts as anti-mycobacterial and anti-tubercular agents
[13–15]. Similarly, In the mechanistic class of DPP-IV inhibitors;
quinazoline moiety in alogliptin, proline group in vildagliptin and
saxagliptin, adamantyl scaffold in vildagliptin have significant role
by forming hydrophobic contacts with amino acid residues in bind-
ing cavity of DPP-IV enzyme [16]. Crystal structure (PDB ID 2ONC)
data revealed good occupancy of the S1 pocket by these substrates
and it was also observed that they preferably reside inside the
hydrophobic cavity consisting of Arg125, Glu205, Glu206, Tyr547,
Tyr662, Tyr666, and Phe357 key residues [17,18].
The objective of the present study was to identify some novel
hits as DPP-IV inhibitors to develop future agents that could serve
as potential treatment option for type2 diabetes mellitus. Structure
based computational approach definitely reduces the expensive
experimental techniques and is also accepted widely in present
research scenario. Therefore, attempt has been made to identify
novel human DPP-IV inhibitors using molecular docking based vir-
tual screening, binding energy and ADME prediction on Chem- Fig. 2. Validation of Docking protocol.
bridge library of 15 lac compounds. Further, molecular dynamics
(MD) simulation studies of the DPP-IV (PDB ID 2ONC) with the
most promising hit molecule was undertaken to evaluate the sta- docking based virtual screening with good resolution of 2.55 Å. The
bility of these complexes and thus obtain the ligand-target selec- active site of 2ONC consists of an approved drug i.e. alogliptin [2].
tivity. To the best of our knowledge, this is the first example of The structure obtained from the PDB was prepared and mini-
successful application of both structure based virtual screening, mized using Protein Preparation Wizard of Schrodinger Drug Dis-
molecular dynamics simulation and knowledge based SAR studies covery suite 2017–2. This resulted in addition of hydrogens, cre-
for the identification of novel DPP-IV inhibitors. ation of disulfide bonds, assigning of proper bond orders, removal
of water molecules beyond 5Ǻ, optimization and minimization of
hydrogen bonds to remove any steric hindrances in the protein
2. Material and methodology structure. The filling of missing side chains and loops was done
by using Prime module [19].
2.1. Structure-based approach The prepared structures of human DPP-IV (2ONC) were used for
docking studies. 3D grid was created around the co-crystallized in-
The crystal structure of human dipeptidyl-peptidase-IV enzyme hibitor (alogliptin). Alogliptin binding site in receptor was found to
(hDPP-IV, PDB ID 2ONC) was obtained from protein databank for be located in central core of ligand binding domain which revealed
 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006 3

good occupancy of the S1 pocket by substrate and that, these drugs
reside inside with some key residues such as Arg125, Glu205,
Glu206, Tyr547, Tyr662, Tyr666, Ser630, and Phe357 [17,18]. The
size of grid was kept default at 20 Å. This site defines the binding
site of the hDPP-IV where molecular docking of the Chembridge
library of 15 lac ligand was performed.
Docking protocol was evaluated for robustness by extract-
ing and preparing the co-crystalized inhibitor. The prepared ag-
onist was then docked on the prepared grid of target using SP
docking technique implemented in GLIDE module version 6.9 of
Schrodinger Drug Discovery suite 2017–2. Root mean square de-
viation (RMSD) between the co-crystalized pose of the inhibitor
and the pose generated after SP docking was then calculated [20].
Smaller value of RMSD showed that the docking approach and
scoring function are able to mimic the crystal like pose which fur-
ther verified the correctness of the docking protocol.
2.2. Docking based virtual screening
A library of 15 lac drug-like compounds was used to identify
the potential inhibitor of hDPP-IV. This chemical library was ac-
quired from Chembridge database. This compound library was cho-
sen due to its diverse chemical moiety, thereby resulting in po-
tential hits of diverse chemical scaffolds. Therefore, the screening
would be for the identification of novel scaffolds which could be
taken forward to hit optimization studies. All these chembridge lig-
ands were prepared using LigPrep module version 3.6 for desalt-
ing, cleaning and addition of hydrogen atoms. Various stereoiso-
mers, tautomers and ionization states at pH 7 ± 2 were also gen-
erated [21]. The 3D- grid was generated for docking based virtual
screening at alogliptin binding site. The structure based drug de-
sign, aimed to identify the most potent DPP-IV inhibitor and this
prepared library was subjected to molecular docking on the gener-

Fig. 3. Protein-ligand (PL) interactions; 3a. alogliptin; 3b. ZINC95497396; 3c. ZINC12432646; 3d ZINC72479286; 3e. ZINC12479967; 3f. ZINC95508153; 3 g. ZINC15078132.
4 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006

Fig. 3. Continued

ated target grid using virtual screening workflow of GLIDE module
version 6.9 (Hierarchal screening HTVS, SP, XP) in order to weed
out the molecules on the basis of shape complementarity of the
binding pocket [20].
2.3. In silico ADME studies
The four major concerns in pharmacokinetics are absorption,
distribution, metabolism and excretion (ADME). These four crite-
ria influence the drug levels and kinetics of drug exposure to the
tissues and hence influence the performance and pharmacological
activity of the drug molecule. In silico pharmacokinetic properties
of the hits were predicted using QikProp module version 4.6 by
obeying rule of five and three in order to asses blood brain barrier
permeability, polar surface area, human oral absorption percentage
and molecular weight [22,23].
2.4. Binding energy calculations
The relative binding energy of selected agonists was calcu-
lated from structural information in bimolecular complexes using
Prime module version 4.2 of Schrödinger software. Prime MM-
GBSA (Molecular Mechanics, the Generalized Born model and Sol-
vent Accessibility) is a physics-based method that computes the
force field energies in implicit solvent of the bound and unbound
molecules involved in the binding process. The MM-GBSA bind-
ing energy includes terms such as protein−ligand van der Waals
contacts, electrostatic interactions, ligand desolvation, and internal
strain (ligand and protein) energies. Prime calculates binding ener-
gies using VSGB2.0 implicit solvent model with the OPLS2005 force
field [24,25]. Retrieved hits obtained from docking on 2ONC were
subjected to the MM-GBSA analysis individually. During these cal-
culations, the active site of protein was set to adjust itself up to
 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006 5

Fig. 3. Continued

a distance of 5 Å for ligand accordingly. This operation imports XP
docking “out.maegz” file of protein and ligand complex, which re-
sults in ranking of the ligands based on the calculated binding en-
ergies [25,26].
2.5. Molecular dynamics simulation
The structural stability of the protein-ligand complex was de-
termined by molecular dynamics simulation of most promising
hit, i.e., ZINC72479286 and alogliptin with 2ONC. The 2ONC-
alogliptin and 2ONC-ZINC72479286 complex were solvated using
explicit SPC (simple point charge) water molecules in orthorhom-
bic box. The system 2ONC-ZINC72479286 complex and 2ONC-
alogliptin was neutralized by adding 67Na+ , 56Cl− and 68 Na+ ,
56 Cl− counterions respectively to stabilize the net charge of the
system. After addition of the solvent and counterions, the pre-
pared system of 2ONC-alogliptin and 2ONC-ZINC72479286 com-
pleted for minimization step that contained 52,121 and 52,145
atoms respectively. MD simulation of both complexes was per-
formed for a period of 20 ns with a time-step of 2fs in NPT
(constant number of atoms N, pressure P, and temperature T)
ensemble at 300 K temperature and 1 bar pressure. Tempera-
ture and pressure conditions were maintained by Nose−Hover
chain thermostat and Martyna−Tobias−Klein barostat, respec-
tively. MD simulation was accomplished using multistep prac-
tice present in Desmond software (version 3.8) [21,27,28]. Record-
ing interval of 1.2 ps was used for energy and 4.8 ps were
used for trajectory for every complex. The structural stabil-
ity and target-ligand interactions were analyzed over a pe-
riod of 20 nanoseconds (ns) MD run. MD simulations in-
cluded exhaustive screening workflow of methodology as shown
in Fig. 1.
6 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006

Fig. 3. Continued

Fig. 4. Root mean square deviation (RMSD) of protein ligand complex with both compounds during 20 ns of MD simulation; 4a. RMSD plot of 2ONC-Alogliptin; 4b. RMSD
plot of 2ONC- ZINC72479286.
 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006
Fig. 5. Root Mean Square Fluctuation (RMSF) of protein ligand complex with both compounds during 20 ns of MD simulation; 5a. RMSF plot of 2ONC-Alogliptin; 5b. RMSF
plot of 2ONC- ZINC72479286.
2.6. Knowledge based SAR studies
Knowledge based SAR analysis was done with the help of FDA
approved DPP-IV inhibitor alogliptin, sitagliptin and 3D structure of
hit. Docked orientation of hit compounds and approved drugs were
overlapped in the binding pocket of human DPP-IV protein. Homo-
geneous overlapping of compounds indicated the different features
that required for efficacy and affinity of hit compound [29,30].
2.7. Synthetic feasibility prediction
The easiness of synthetic feasibility of selected hits was pre-
dicted by using Sylvia 1.4 server. Consideration of synthetic possi-
bilities was produced in a number between 1 and 10, lower num-
ber indicate that simply synthesizable compounds, and higher for
compounds that are challenging to synthesize [31].
3. Results and discussion
3.1. Validation of docking protocol
Self-docking of the bound ligand i.e. alogliptin in the 2ONC
crystal structures of DPP-IV under optimized docking parameters
gave RMSD of 2.011 Ǻ along with the dock score of −8.631. The
docked pose of co-crystal ligand is in orange colored ball stick
shape and is overlapped with the co-crystal ligand which is in
green colored ball stick model as shown in the Fig. 2.
3.2. Structure based screening
The direct approach of screening was executed using hierarchal
mode of elimination technique, i.e. high throughput virtual screen-
7
ing (HTVS) followed by simple precision (SP) and the extra preci-
sion (XP). The crystal structure of human DPP-IV (PDB ID 2ONC)
was chosen for target based virtual screening, and it clearly indi-
cated that the compounds having diversity in their structures were
able to form bonds with different amino acids in S1 pocket. The
active site of hDPP-IV was determined using co-crystallized ligand
i.e. Alogliptin, which is the FDA approved drug (IC50 7 nM). Amino
acids which played key role for the inhibition of hDPP-IV enzyme
were mainly Glu 205, Glu 206, Arg 125, Tyr 547 and Try 631 of S1
pocket.
Using extra precision (XP) mode of docking, 132 compounds
were retrieved in hierarchal structure based virtual screening from
the chosen Chembridge library of 15 lac diverse compounds. These
compounds were obtained on the basis of affinity, pose, glide en-
ergy, dock score and other calculated penalties between the target
and ligand.
3.3. Post processing hierarchical structure based screening
Weed-out processing included ADME prediction and binding
energy calculations. These screening processes of hits against
hDPP-IV enzyme were done by using QikProp module version 4.6
of Schrodinger. Out of 15 lac compounds from chembridge library,
only 06 potential hits were considered on the basis of different
type of interactions obtained between enzyme and the ligand as
illustrated in Table 1. ADME predicted data and predictive bind-
ing energy are shown in Table 2. Based on similar interaction,
scores and admissible ADME, Compound 3 was selected for fur-
ther MD simulation studies as supported by the pose and orien-
tation of compound 3 in binding cavity of 2ONC. Moreover, Com-
pound 3 showed best results in 2D and 3D contacts with protein as
8 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006

Fig. 6. Contacts of protein ligand complex with both compounds during 20 ns of MD simulation; 6a. 2D-contacts of 2ONC-Alogliptin; 6b. 2D-contacts 2ONC- ZINC72479286;
6c. Different interaction between 2ONC-Alogliptin; 6d Different interaction between 2ONC - ZINC72479286.

Table 1 Glu205, Glu206 showed hydrogen bonding in Alogliptin-DPP-IV

Protein-ligand (PL) interactions of drug and retrieved hits with their compound IDs.
contacts. These targeted compounds as depicted in Fig. 3 may
S. No. Compound ID P-L Interacting Residues serve as effective and potential hits for DPP-IV inhibition and this
Ref. Alogliptin Tyr666, Tyr547, Tyr631, Glu205, Glu206 process would also prove useful in lead finding process of drug de-
1 ZINC 95497396 Tyr666, Glu205, Glu206, Phe357 velopment procedure for diabetic population.
2 ZINC 12432646 Tyr666,Glu205, Glu206,Phe357, Ser209
3 ZINC 72479286 Tyr666, Glu205, Glu206, Phe357, Tyr547
4 ZINC 12479967 Tyr547, Tyr666, Glu206, Phe357
3.4. Molecular dynamics simulation
5 ZINC 95508153 Tyr666, Glu205, Glu206, Phe357, Arg125
6 ZINC 15078132 Arg125,Tyr662,Try666, Glu206
Diverse aspects were evaluated in MD simulation examination,
which mainly included the stability strength of protein-ligand by
analyzing root mean square deviation (RMSD) of backbone and
root mean square fluctuation of side chain residues. Molecular
compared to compound 1 and compound 2. Tyr547, Glu205, dynamics simulation studies of 2ONC with drug candidate, i.e.
Glu206 showed hydrogen bonding interactions and Tyr666 showed Alogliptin along with MD simulation of obtained best hit candidate
pi-pi bonding with compound 3 i.e. ZINC 72479286 whereas, (ZINC72479286) from exhaustive in silico screening against the tar-
Tyr547, Tyr666, Tyr662, Tyr631 showed pi-pi interaction while get were performed.
 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006 9

Fig. 6. Continued

3.4.1. MD simulation of complex hDPP-IV (2ONC) with Alogliptin and
ZINC72479286
Evaluation of the RMSD of the protein backbone with respect
to the initial frame of protein structure was carried out so as to
establish the stability of the protein complexes with bound in-
hibitor at the alogliptin binding site. Further, the structural sta-
bility of the enzyme complexes was analyzed based on the RMSD
and RMSF values of enzyme and ligands during the simulations.
The RMSD value of protein backbone was found to be stabilized
below 2 Ǻ. For the stable trajectories of both complexes i.e. in-
dividual alogliptin and ZINC72479286, RMSD were obtained be-
low 2.0 Ǻ as shown in Fig. 4(a) and (b). Binding energy of these
ligands with protein was calculated using Prime MM-GBSA and
was found to be −81.986 and −74.057 kcal/mol for alogliptin and
ZINC72479286 respectively. RMSF of both ligands with 2ONC com-
plexes were found to have stable trajectories during the 20 ns MD
run. RMSF plot of side chains residues of protein showedleast
amount of fluctuations i.e. below 2 Ǻ as shown in Fig. 5(a)
and (b). Protein- Ligand interactions that were maintained during
20 ns MD simulation were examined. Residues ARG125, GLU205,
GLU206, T YR547, T YR631, SER209, GLY632 and GLU204were in-
volved in interaction with alogliptin as shown in Fig. 6(a) and (c).
Residues GLU205, GLU206, T YR547, T YR666,and PHE357 formed
various interactions with ZINC72479286. TYR631, GLU206 and
GLU205 formed hydrogen bonded contacts while SER209, TYR547,
GLY632 and GLU204 formed water bridges whereas TYR547 and
ARG125showed pi-pi interactions. Residues GLU205 and GLU206
were involved in hydrogen bonding interaction with ZINC72479286
as shown in Fig. 6(b) and (d). Residues T YR662, T YR666 and
HIS126 formed pi-pi stacking with ZINC72479286while residues
PRO550 and TYR662 form contact through water bridge with
ZINC72479286.

Table 2
Dock score, Binding energy and ADME calculation.

S.No. ID Dock score Binding energy QPlogPo/w QPlogS QPlogHERG QPPCaco QPlogBB QPPMDCK PercentHumanOralAbsorption QPlogKp

1 95,497,396 −11.007 −83.978 2.582 −3.056 −5.898 320.861 −0.528 160.183 86.923 −4.012
2 12,432,646 −10.474 −84.966 2.955 −1.212 −6.331 135.692 −0.048 69.904 82.419 −4.882
3 72,479,286 −10.463 −74.057 3.484 −3.071 −7.136 172.125 0.494 90.395 87.36 −5.205
4 12,479,967 −10.378 −97.465 3.116 −2.73 −7.647 89.819 −0.056 69.06 80.151 −5.551
5 95,508,153 −10.417 −102.867 1.832 −1.051 −6.057 108.34 −0.133 54.806 74.089 −5.723
6 15,078,132 −9.183 −99.918 3.893 −2.527 −5.769 314.172 0.472 173.224 94.433 −5.009
10 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006

Table 3
Depicting predicted synthetic accessibility score with their compound IDs and structures.

S.No. Compound ID Structures Synthetic accessibility score

Alogliptin 4.85

1 ZINC 95497396 4.01

2 ZINC 12432646 4.08

3 ZINC 72479286 3.69

4 ZINC 12479967 4.97

5 ZINC 95508153 4.29

6 ZINC 15078132 4.75

 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006 11

Fig. 7. Knowledge based SAR studies. a. Surface view of binding cavity with Alogliptin, Sitagliptin and ZINC72479286; b. 2D structures of drugs for assessment of important
pharmacophoric features in ZINC72479286.

3.4.2. Knowledge based SAR studies
FDA approved drugs (alogliptin and sitagliptin) were used for
knowledge based SAR analysis and it was done by the evaluation
of orientation and pose of these drugs in the binding pocket along
with overlapping of retrieved candidate compound. Coinciding of
these compounds (alogliptin is in red and sitagliptin is in yellow
color) in the binding pocket revealed the fitness and shape com-
plementarity, which is considered essential for the affinity of hit
candidate (purple color) and drugs. Further, 2D structural features
of alogliptin and sitagliptin was also matched with best obtained
hit compound and it resulted in the similar chemical features of
drugs and hit compound.
Modification with fused heterocyclic or bicyclic ring system
with hetero atom in yellow region would be favored, electron
withdrawing group(s) may be useful for substitution at green col-
ored region, the essentiality of orange colored site may be replace-
able from any cyclic ring or elongated carbon chain with or with-
out heteroatom, purple region is essential for pi-pi interaction with
key amino acids residues in the a binding pocket of DPP-IV en-
zyme, therefore, insertion of aromatic system may produce a po-
tential inhibitor. The pink colored region is not essential for any
type of substitution as electron withdrawing group or donating
group were not involved in any kind of interactions as depicted
in Fig. 7(a) and (b). Knowledge based SAR studies may be helpful
12 V. Nath, M. Ramchandani and N. Kumar et al. / Journal of Molecular Structure 1224 (2021) 129006
in designing and synthesis of novel DPP-IV inhibitors with more
selectivity and efficacy.
3.4.3. Sylvia—Synthetic accessibility estimation
The synthetic feasibility of retrieved hit compounds along with
alogliptin had predicted scores as showed in Table 3. This finding
is similar to that of alogliptin that may be a valuable forward for
the future synthesis with the feasible economic route.
4. Conclusion
The present study aimed to identify the best possible com-
pounds as DPP-IV inhibitor from the chembridge library of
drug like compounds. Six thriving molecules were identified
using structure based drug design tools and it was observed
that among these six molecules, Compound 3 i.e. [(2-(3-((4-(1-
methyl-1H-benzo[d]imidazol-2-yl) piperidin-1-yl)methyl)phenyl)
ethanamine)] exhibited the best dock score, i.e. –10.463 K.cal/mol
with DPP-IV (PDB ID-2ONC) and thus, was evaluated further for
protein-ligand interactions, ADME and predicted binding energy.
In addition, MD simulation was done to confirm the protein-ligand
complex stability. The RMSD of both, 2ONC with alogliptin and
compound 3 were found to be below 2.0 Å. Further, knowledge-
based SAR studies revealed the vital regions of binding pocket
and thus, the diverse substitution sites in retrieved hits were
identified for the selection of more druggable compounds. These
retrieved compounds have cyclic or heteroaromatic ring which
formed hydrophobic contacts in the binding pocket of DPP-IV
enzyme. Piperidine ring was present in sitagliptin and it was also
present in the retrieved molecules 1, 3, 4, 5 and 6. Molecule 2
have proline moiety which was also present in vildagliptin and
saxagliptin. Cyclized nitrile group was illustrated in molecule 3 as
present in open form in alogliptin. Therefore, these compounds
may have inhibitory potential against the DPP-IV enzyme as
they have diversity in their structure and resemblance with the
previously approved drugs. The predicted synthetic accessibility
score also proved the ease of synthetic feasibility of compound 3
as compared to the other hit candidates. The results obtained in
the present study support the design of newer DPP-IV inhibitors
as anti-diabetic lead compound.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
Virendra Nath: Conceptualization, Methodology, Validation,
Data curation, Writing - original draft. Manish Ramchandani: Data
curation, Visualization. Neeraj Kumar: Validation, Visualization.
Rohini Agrawal: Writing - review & editing. Vipin Kumar: Project
administration, Resources.
Acknowledgement
I am thankful for the funding as Senior Research Fellow grant
from Council of Scientific and Industrial Research, Government of
India (File no. 09/1131(0027)/19-EMR-I).
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