International Journal of Research in Engineering, Science and Management 445

Volume-2, Issue-2, February-2019

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Role of Computer Aided Drug Design in Drug

Development and Discovery: An Overview
Sameera Begum1, S. M. Shahidulla2
1
Student, Department of Pharmaceutics, Deccan School of Pharmacy, Hyderabad, India
2
HoD, Department of Pharmaceutics, Deccan School of Pharmacy, Hyderabad, India

Abstract: The process of drug development and discovery is very Fast expansion in this area has been made possible by
challenging, expensive and time consuming. It has been advances in software and hardware computational power and
accelerated due to development of computational tools and sophistication, identification of molecular targets, and an
methods. Over the last few years, computer aided drug design also
known as in silico screening had become a powerful technique. increasing database of publicly available target protein
This review provides an insight about developmental chain, structures. CADDD is being utilized to identify hits (active drug
approaches and applications of CADD, various data sources, candidates), select leads (most likely candidates for further
computational method for the discovery of new molecular entities. evaluation), and optimize leads i.e. transform biologically
The crucial steps of in silico drug designing like docking, multi- active compounds into suitable drugs by improving their
target searching and design, pharmacophore development, physicochemical, pharmaceutical, ADMET/PK
conformation generation, quantitative structure activity
relationship(QSAR). (pharmacokinetic) properties. Virtual screening is used to
discover new drug candidates from 3-dimensional chemical
Keywords: Drug discovery, Computer aided drug design, structure databases. It is intended to reduce the size of chemical
Docking, multi-target searching, QSAR. space and thereby allow focus on more promising candidates
for lead discovery and optimization. The goal is to enrich set of
1. Introduction molecules with desirable properties (active, drug-like, lead-
The drug discovery process is a very complex and includes like) and eliminate compounds with undesirable properties
an inter disciplinary effort for designing effective and (inactive, reactive, toxic, poor ADMET/PK. The rapid growth
commercially feasible drug. In pharmaceutical medicinal as of virtual screening is evidenced by increase in the number of
well as in other scientific research; a computer plays a very citations matching keywords “virtual screening.
important role even in development of new compound in quest A. Brief history of CADD
for better therapeutic agent [1]-[3].
For this purpose, Computer Aided Drug Design [CADD]  In 1900: the concept of receptor and lock-and-key was
Centre works with collaboration between structure biologists, given by P.Ehrich (1909) and E. Fisher (1894).
biophysicists and computational scientists for discovery of new  1970s: the concept of Quantitative structure-activity
chemical entities. CADD and bioinformatics tools provide relationships (QS- AR) was established, it had
benefits of drug receptor interactions, speed up drug discovery Limitations: 2- Dimensional, retrospective analysis.
and development [4], [6].  1980s: Beginning of an era of CADD Molecular
CADDD will be employed in this overview of the area to Biology, X-ray crystallography, multi-dimensional
cover the entire process. Both computational and experimental NMR Molecular modeling along with computer
techniques have important roles in drug discovery and graphics.
development and represent complementary approaches. CADD  1990s: modern techniques like Human genome
entails: Bioinformatics along with combinatorial chemistry
1. Use of computing power to streamline drug discovery and High-throughput screening were introduced in the
and development process. world of innovative medical science.
2. Leverage of chemical and biological information B. Benefits of CADD:
about ligands and/or targets to identify and optimize
 Cost savings many biopharmaceutical companies use
new drugs.
CADD in order to reduce cost burden [7].
3. Design of in silico filters to eliminate compounds with
undesirable properties (poor activity and/or poor  Traditional experimentation requiring animal and
Absorption, Distribution, Metabolism, Excretion and human models are now replaced by CADD, which
Toxicity, ADMET) and select the most promising saves both time and cost [8].
candidates.  It is hoped that in case of certain diseases like
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Volume-2, Issue-2, February-2019
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influenza, computational drug designing will play an compounds, whether to increase bio affinity and
important role in reducing the chances of drugs pharmacokinetic properties like absorption,
resistance and thus would lead to production of lead distribution, metabolism, excretion (ADME) as well
compounds which would target the causative factor as toxicity knowledge.
[8].  Designing of novel compounds containing one
 CADD has also led to construction of high quality data functional group in a chemical compound or new
sets and libraries that can be optimized for high chemo types by joining different fragments [15].
molecules diversity or similarity [9].
2. Working of computer aided drug design
C. Limitations in CADD
 Lack of accurate experimental data that restricts A. Stages of computer aided drug design
further advancements of CADD [10].
 Some procedures concerning computer Aided drug
designing are time consuming, especially while
looking for a proper lead component [11].
D. Approaches used in rational drug design
1) Known 3-D structure of protein

Fig. 3. Working of CADD

Computer aided drug designing process consists of 3 stages:

Stage 1: Involves identification of therapeutic target and
Fig. 1. Approach of drug design with known target building a heterogenous small molecule library to be tested
2) Structure of 3-D protein is not known (For new molecule) against it. There is development of virtual screening protocol
initialized by docking of small molecules.
Stage 2: The selected hits are checked for specificity by docking
at binding sites of other known drug targets.
Stage 3: The selected hits are subjected to computational
ADMET profiling studies and those who pass these studies are
called leads.
Target Identification–It is the first key stage in the drug
discovery pipeline. Identification of correct targets from
thousands of candidate macromolecules is a tedious process,
Fig. 2. Approach of drug design with unknown target
which can be achieved by literature referring, Genomic
analysis, and pathway analysis [13].
After the above two approaches those have been shown in Target Validation–After target identification, a rigorous
(Fig. 1) and (Fig. 2), following properties are required to be evaluation is needed to demonstrate that modulation of target
checked for the examination of drug like properties in will have desired therapeutic effect. Target validation process
compound: determines whether modulation of target will have desired
 Examination of QSAR, potency, docking and scoring, therapeutic effect.
multi - regression analysis. Lead optimization–Leads can be identified with the help of
 Reactivity evaluation like nucleophile, electrophilic techniques like Structure based design. At this point, the
and radial attack. structure of the target protein in complex with the lead molecule
can be extremely useful in suggesting ways to improve the
 Preclinical evaluation [12]-[14].
affinity of the lead for the target. Leads which are used in this
E. Significance of CADD in drug discovery and development case may be far from perfect, thus they should be optimized in
 Filtration of large compound libraries into smaller order to increase their affinity for the target sites. Optimization
compounds sets of predicted activity those could be may be obtained by altering their structural features [14].
further tested experimentally. IN SILICO ADMET (Absorption, Distribution, Metabolism,
 Gives information about optimization of lead Excretion, Toxicity) –Prediction Techniques like molecular
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modelling, data modelling are used to study the interaction of In rigid docking the internal geometry of both the receptor
proteins involved in ADMET process [15]. and ligand are targeted as rigid. Both the receptor and ligand is
maintained fixed and docking is executed.
Multi-target Drug Searching and Designing Through CADD: (2) Flexible Docking (Induced fit)
The CADD technique is very useful in; searching drugs In induced fit docking both the ligand and the receptor are
against multiple targets could be performed in which various conformationally flexible. An enumeration on the rotations of
hits are generated against multiple targets. In which the true- one of the molecules (usually smaller one) is performed and
hits rates should be high than comparison to false- hits rates energy is calculated; later the most optimum pose is selected.
against of targets because it is needed in searching of multi- Docking can be between
target searching for enrichment [16]-[18].  Protein-Ligand

Drug - receptor interaction analysis through CADD:

Experimental work, analysis and computer simulation used
for information of drug- receptor interaction and finding a new
active compound.
After acquiring knowledge of bio molecular structure bio
molecular docking is performed; which involves confirmation
and orientation ‘pose’ of small molecule (ligand) in the cavity Fig. 6. Protein-Ligand Docking
(active site) of target protein.
Docking is used to identify and optimize drug candidates by  Protein-Protein
examining and modeling molecular interactions between
ligands and target macromolecules.
Structure (target)-based design requires structural
information for the receptor which can be obtained from X-ray
crystallography, NMR or homology modeling.

Fig. 7. Protein-Protein Docking

 Protein-Nucleotide

Fig. 4. Docking with receptor and ligand

Fig. 8. Protein-Nucleotide Docking
Molecular docking can be separated into two sections as
shown in the figure below, These are the following types could be:
 Protein docking: Most of the computer studies needed
protein which is involve in docking because majority
of structures are known.
 Protein - protein docking: In this, two proteins bodies
are assumed as two rigid solid bodies also with the
help of geometric surface models and data structures
binding mode is selected.
 Protein - ligand docking: It gives accurately analysis
about molecular interaction. Here complementary
contact surfaces are smaller than protein-protein
docking. Small ligand adapt surface of receptor and fit
Fig. 5. Molecular docking into complementary site (ligand should be flexible
B. Types of docking molecule).
The following are primarily applied methods for docking:  Other important phenomenon than structure
(1) Rigid Docking (Lock and Key) flexibility: Presence of single water molecules
between ligand molecule and protein molecule leads
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to complex formation and plays an important role because wrong shape prevents fitting of compound into the
[19]-[21]. receptor [28].

Pharmacophore Development Through CADD: Quantitative Structure Activity Relationship (QSAR) Studies
Pharmacophore is defined as the three-dimensional Through CADD:
arrangement of chemical functional groups which is responsible For many cases in which structural based approaches are not
of biological activity. Now a days pharmacophore model (has applicable because of absence of target macromolecule
been shown in Fig. 9) development has become an important structure information, in those cases QSAR approach is used
part of drug discovery, design, optimization and development [29], [30].
[22], [23]. Through the CADD, screening of Pharmacophore is QSAR gives information about relationship between
performed which contains different scaffold containing chemical structure and biological activity in the form of a
compound but contains similar 3-D functional group mathematical expression. The main advantages of QSAR
arrangement [24], [25]. Pharmacophore methods find different method is to identification of properties of novel chemical
types of compounds having common arrangement. Before compounds in which there is no need of synthesis and testing of
using generated pharmacophore it should be validated with them [31].
external data. If any suitable pharmacophore formed, virtual Clinically Approved Drug Discovered Through CADD
screening fastens [26], [27]. Approaches:
IUPAC defines pharmacophore as: “the ensemble of steric Some examples of clinically approved drugs with year of
and electronic features that is necessary to ensure the optimal approval and therapeutic actions developed through CADD
supramolecular interactions with a specific biological target approaches.
structure and to trigger (or to block) its biological response. The
pharmacophore can be considered as the largest common Applications:
denominator shared by a set of active molecules.” Bioinformatics in Computer-Aided Drug Design: CADD
methods are heavily dependent on bioinformatics tools,
application and on the support side of the hub, information
technology, information management, software applications,
databases and computational resources all provide the
infrastructure for bioinformatics. On the scientific side of the
hub, bioinformatics methods are used extensively in molecular
biology, genomics, proteomics, other emerging areas (i.e.
Metabolomics, transcriptomics) and in CADD research. There
are several key areas where bioinformatics supports CADD
Fig. 9. Example of pharmacophore model
research.
A pharmacophore gives good knowledge about molecular  Graph Machines for the Prediction of activities of
interactions of various compounds to their target structure and molecules: In the past few years, QSAR has become a
these features are complimentary to each other in 3-D space. major field of research in the chemical industry. In a
Pharmacophore could be more better though combination with typical QSAR/QSPR scenario, a database of measured
shape and volumes for proper fitting into the site of the receptor properties or activities of molecules is available, and it
is desired to infer, from those data, the
Table 1
List of some clinically approved drug discovered though CADD approaches [32]-[34]
Drug year of approval Therape-UTIC action
Captopril 1981 Antihypert-ensive
Saquinavir 1995 Human immunodef-icieny Virus (HIV) inhibitor
Indinavir 1996 Human immunodeficiency Virus (HIV) inhibitor
Aliskiren 2007 Human rennin inhibitor
Boceprevir Phase III clinical trials Hepatitis C virus (HCV) inhibitor
Nolatrexed Phase III clinical trials In Liver cancer

Table 2
Different tools and databases [10]
Tool Brief description with uses
BLAST Basic local alignment search tool; used for sequencing of DNA and protein
Discovery studio Software; used for modelling and simulation
Pub Med Free search engine; used for searching matter related to medical and life sciences
PDB Protein data bank; used to collect information related to macromolecule
Chem Draw Part of the Chem office programs; used to draw chemical molecule
Auto Dock Software; used for molecular docking
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