COMPUTER-AIDED DRUG DESIGN (CADD)

 Comprises a broad range of theoretical and computational approaches that are part of modern drug
discovery
 CADD methods have made key contributions to the development of drugs that are in clinical use or in
clinical trials
 such methods have emerged and evolved along with experimental approaches used in drug
 CADD is an exciting and diverse discipline where various aspects of applied and basic research merge and
stimulate each other
 In the early stage of a drug discovery process, researchers may be faced w/ little or no structure activity
relationship (SAR) information
Drug Design
 often referred to as rational drug design or simply rational design
 is the inventive process of finding new medications based on the knowledge of a biological target
 the drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule
such as a protein, w/c in turn results in a therapeutic benefit to the patient
 in the most basic sense, drug design involves the design of molecules that are complementary in shape and
charge to the biomolecular target w/ w/c they interact and therefore will bind to it
 drug design frequently but not necessarily relies on computer modeling techniques
 this type of modeling is sometimes referred to as computer-aided drug design
 finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target
is known as structure-based drug design
 Furthermore, in vitro experiments complemented w/ computation methods are increasingly used in early
drug discovery to select compounds w/ more favorable ADME (absorption, distribution, metabolism, and
excretion) and toxicological profiles
 CADD has been credited to the modern patterns in compound characterization in drug discovery following
its inception in 1981
 it represents an advancement when compared to HITS as it requires minimal compound design or prior
knowledge, but can yield multiple HIT compounds among w/c promising candidates have been elected
 the typical role of CADD in drug discovery is to screen out large compound libraries into smaller clusters of
predicted active compounds, enabling optimization of lead compounds by improving the biological
properties (like affinity and ADMET) and building chemotypes from a nucleating site by combining fragments
w/ optimized function
 Clustering has been applied as a means to select representatives from screening libraries
 screening HITS include molecules that specifically bind to the target in addition to a greater number of
nonspecific compounds requiring a triaging process to filter theses out thus, such a large library that
contains a number of possible HITS is further downsized and clustered into series
 Computational chemistry algorithms have been developed to group HITS based on structural similarity, w/c
is necessary to ensure that compounds are adequately sorted over a broad spectrum of chemical classes
 thus, selection of HITS would be based on chemical cluster, potency, and factors such as ligand efficiency
(w/c gives an idea of how well a compound bind for its size)
 the increasing application of diverse computerized methods in drug discovery has enabled a better handling
of data associated w/ a large number of compounds screened against the target molecules or proteins for
leads
 computational tools help to define and elaborate the strength of interaction between ligands and targets and
have been instrumental in the ID of lead molecules from databases
  nevertheless, the lack of specificity leads to low HIT rate for HTS, w/c could limit its applicability and
efficiency in screening large compound libraries
 CADD is a more targeted approach to the generation of 'HITS' when compared w/ traditional HTS
 it enables the elucidation of the molecular basis of therapeutic activity and possible derivatives and those
variables that could be applied or improved for generating an optimal drug compound, thus leading to
prioritization of the actives w/out requiring extensive development and validation prior to use, as in the case
of assay HTS
 the CADD approach has played a vital role in the search and optimization of potential lead compounds w/ a
considerable gain in time and cost
 it has been applied during various stages in drug discovery: target ID, validation, molecular design and
interactions of drug candidates w/ targets of interest
 CADD can be structure or ligand based
 Structure-Based CADD seeks the knowledge of the target protein structure in the determination of
interaction levels of all compounds being examined
 Ligand-Based CADD relies on the chemical similarity criteria and the predictive quantitative structure-activity
relations (QSAR)models that it creates from the molecules to determine the known active and inactives
 QSAR modelling enables understanding of the influence of structural factors on biological activity, using the
models and the understanding to construct compounds w/ improved and optimal biological profiles
 other methods for quantitative description of structural change are comparative molecular field analysis and
grid effects and that could be designed w/ minimal free energy, favorable drug metabolism and
pharmacokinetic/ADMET properties
 in general, CADD is better suited for occasions where sparse structural information is available
 this is usually the case for membrane protein targets computer aided drug design (CADD)
 helps scientists in minimizing the synthetic and biological testing efforts by focusing only on the most
promising compounds
 besides explaining the molecular basis of therapeutic activity, it also predicts possible derivatives that would
improve activity
 structure-based CADD is preferred choice for soluble proteins that could be crystallized, while ligand-based
CADD is better suited for compounds w/ high binding affinity to the target devoid of off-target CADD entails:
1. Drug discovery and development processes being streamlined by the use of computing power.
2. Identification and optimization of new drugs using leverage of chemical and biological information
about target and/or ligands.
3. In silico designing of filters for the elimination of undesirable compounds w/ properties like poor
activity and/or poor absorption, distribution, metabolism, excretion, and toxicity, ADMET w/c
facilitate selection of the most promising candidates.
ADVANTAGES OF CADD
 The main advantages of drug discovery through CADD are:
1. For experimental testing smaller set of compounds are selected from large compound libraries.
2. Drug metabolism and pharmacokinetics (DMPK) properties like absorption, distribution,
metabolism, excretion, and the potential for toxicity (ADMET) are increased by optimization of lead
compounds.
3. Designing of novel compounds can be achieved either by "growing" starting molecules one
functional group at a time or by piecing together fragments into novel chemotypes.
4. Traditional experimentation w/c requires animal and human models can be replaced by CADD,
saving both time and cost
 5. Reduces the chances of drug resistance and thus would lead to production of lead compounds w/c
would target the causative factor.
6. CADD also leads to the construction of high-quality datasets and libraries that can be optimized for
high molecular diversity or similarity
Types of CADD
 the choice of CADD approaches to be employed is determined by the availability of the experimentally
determined 3D structures of target
There are 2 major types of Drug Design
1) Ligand-based drug design and
2) Structure-based drug design

Ligand-based (Indirect Drug Design)

 relies on knowledge of other molecules that bind to the biological target of interest
 these other molecules may be used to derive a pharmacophore model that defines the minimum necessary
structural characteristics a molecule must possess in order to bind to the target
 in other words, a model of the biological target may be built based on the knowledge of what binds to it and
this model in turn may be used to design new molecular entities that interact w/ the target
 alternatively, a quantitative structure-activity relationship (QSAR), in w/c a correlation between calculated
properties of molecules and their experimentally determined biological activity, may be derived
 these QSAR relationships in turn may be used to predict the activity of new analogs

Structure-Based (Direct Drug Design)

 relies on knowledge of the three-dimensional structure of the biological target obtained through methods
such as x-ray crystallography or NMR spectroscopy
 if an experimental structure of a target is not available, it may be possible to create a homology model of the
target based on the experimental structure of a related protein
 using the structure of the biological target, candidate drugs that are predicted to bind w/ high affinity and
selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist
 alternatively various automated computational procedures may be used to suggest new drug candidates
 Structure-Based CADD uses our knowledge of the target protein structure to calculate interaction energies,
whereas in ligand-based CADD chemical similarity searches or construction of predictive, Quantitative
Structure Activity Relationship (QSAR) models exploits our knowledge of known active and inactive
 Structure-Based CADD combines information from several fields for example, x-ray crystallography and/or
NMR, synthetic organic chemistry, molecular modelling, QSAR and biological evaluation
 through structure based CADD, we aim to design compounds w/ strong binding affinity w/ the target, thereby
exhibiting properties like reduced free energy, improved DMPK/ADMET properties and target specification
i.e. reduced off-target
 Virtual High-Throughput Screening (VHTS) also known as screening of virtual compounds libraries is one of
the most common applications of CADD
 Drug discovery process usually starts w/ an analysis of binding sites in target proteins or an identification of
structural features common to active compounds
  the process ends w/ the generation of small molecule "Leads" suitable for further chemical synthetic work
 it is a recent and emerging discipline that uses several bioinformatics tools and related fields like chemi
informatics and combinatorial chemistry
 CADD uses computational chemistry to discover, enhances or study of drugs and related biologically active
molecules
Role of CADD
 the target of computer assisted drug design (CADD) is not to find the ideal drug but to identify and optimize
lead compounds and save some experiments
 the parameters expected from a drug are:
 Safety
 Efficiency
 Stability
 Solubility
 Synthetic viability
 Novelty
 Drug designing approaches > there are four basic approaches for drug designing
1. Ligand based approaches
2. Target based approaches
3. De novo approaches
4. SBDD
Ligand Based Approach
 these are used when the receptor is not known
 Ligand based approaches try to identify characteristics common to known ligands to use in screening for
new or improved drugs
 if a set of active ligands molecules is known for the macromolecular target, but little or no structural
information exists for the target
 Ligand based computational method can be employed
There are two methods to do this:
1. Quantitative Structure Activity Relationship (QSAR) method
2. Pharmacophore method -> 3-D arrangement of functional groups w/in a molecular framework that are
arrangement of specifically bind to a macromolecule or an enzyme active site
 Identification of a chromophore is an important step in the interaction between a receptor and a ligand
Target Based Approaches
 Target based drug design methods based on the structure of the biological target either bound or unbound
to an inhibitor or substrate
 Are also known as Structure Based or Rational Design Methods
Docking
 refers to the ability to position a ligand in the active or designated site of a protein and calculate the specific
binding affinities
  Docking algorithms can be used to find ligands and binding conformations at a receptor site close to
experimentally determined structures
 Docking algorithms are also used to identify multiple proteins to w/c a small molecule can bind
 involves scanning a database of known molecules for those likely to bind well to the receptor
 is used to generate possible binding geometries and can evaluate using a scoring
 Function: The method may also involve one refinement of the initially generated conformations before or
after scanning
De Novo Approaches
 De Novo Design is the approach to build a customized ligand for a given receptor
 this approach involves the ligand optimization
 ligand optimization can be done by analyzing protein active site properties that could be probable area of
contact by the ligand
 the analyzed active site properties are described to negative image of protein such as hydrogen bond,
hydrogen bond acceptor and hydrophobic contact region
Structure Based Drug Design
 Structure-based drug design (SBDD, also known as Rational drug design) is a technique that accelerates
the drug discovery process by utilizing structural information to improve the lead optimization process
 it has been estimated that SBDD can reduce the cost from target ID to investigational new drug (IND) filling
by 50%
 the technique requires high resolution 3-D structure of the inhibitor bound to the target obtained using x-ray
crystallography