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Computer Aided Drug Design Textbook of Computer Aided Drug Design Computer Aided Drug
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 Textbook of

Textbook of
Computer Aided Drug Design for BPharm Students
is much-awaited textbook in the drug design course in pharmacy. Targeted mainly at the BPharm
students, this book will also be helpful for students of MPharm, BSc and MSc in chemistry and
pharmaceutical chemistry courses. The book provides complete information for learning and teaching
the subject of computer-aided drug design.
Salient Features
Content of the book is innovative and presented in five units, in a detailed form as per the Textbook of

Computer Aided Drug Design Students

requirements of the students, and in compliance with the latest syllabus prescribed by Pharmacy

Computer
Council of India (PCI).
Book has covered the entire subject of computer-aided drug design, starting from introduction to
drug discovery and development, stages of drug discovery and development to molecular
modeling.
Drug discovery and development methods are explained in a stepwise and simplified manner.
Principles of computer-aided drug design, though difficult to remember, are described in a

Aided
student-friendly manner that is easy to understand and reproduce well in examinations.
Includes flowcharts and schematic representations of drug design for easy assimilation.
The subject is well explained with modern concepts of drug discovery and development.

V Raja Solomon received his BPharm from SB College of Pharmacy, affiliated to The Tamil Nadu Dr MGR
Medical University, Chennai, India, and MPharm with a specialization in medicinal and pharmaceutical
chemistry from the Shri GS Institute of Technology & Science, Indore, affiliated with Rajiv Gandhi Technical

Drug Design
University, Bhopal, India, under the direction of Prof SC Chaturvedi. He completed his PhD in the field of
medicinal chemistry at the CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, India, under Prof SB
Katti. He moved to the Prof Hoyun Lee research group at Health Science North Research Institute, Sudbury,
Ontario, Canada for his postdoctoral studies. He has received the prestigious Postdoctoral Research Award
from the Ontario Government, Ministry of Research and Innovation. He has received a prestigious foreign
researcher award from Japan Society for the Promotion of Science (JSPS) and worked for two years at Nagoya
City University with Prof Naoki Miyata. He worked as a research associate at the University of Sydney, NSW,
Australia, with Prof Jane Hanrahan for three years. He also worked as a research scientist at the Department of
Medical Imaging, University of Saskatchewan, Saskatoon, SK, Canada. He is the author/co-author of over
75 papers, 3 review articles, 3 book chapters, and 1 patent, including the original research articles and
presentations in various national and international conferences and symposiums. His research interest
includes QSAR and molecular modeling, drug design, cancer drug discovery, synthetic organic chemistry,
for BPharm Students
medicinal chemistry and radiochemistry.

V Alagarsamy MPharm, PhD, FIC, DOMH is Professor and Principal, MNR College of Pharmacy and Director, As per the latest syllabus prescribed by Pharmacy Council of India
MNR Foundation for Research and Innovations, Gr. Hyderabad. He has been teaching medicinal chemistry
and pharmaceutical chemistry of natural products and performing research work in synthetic medicinal
chemistry on novel heterocyclic bioactive compounds for more than two decades. He is the author/co-author
of over 200 papers, including the original research articles and presentations in various conferences and
symposiums, having one patent for his credit on bioactive heterocyclic molecule. He is the coeditor of the
international journal Antiinfective Agents published by Bentham Science Publishers. His books Textbook of
Medicinal Chemistry, Pharmaceutical Chemistry of Natural Products, Pharmaceutical Inorganic Chemistry,
Organic Chemistry: A Comprehensive Approach, Pharmaceutical Organic Chemistry and Practical
Pharmaceutical Inorganic Chemistry are well appreciated in the academic community nationally and have

for BPharm
also received international recognition. He is a member of All India Board of Pharmaceutical Education (AIB-
PE), AICTE, New Delhi, and a member of board of studies (pharmacy) in Osmania University, Hyderabad, and is
a doctoral committee member and a recognized research guide for PhD scholars in various universities.
Recently, he has been named among top 2% scientists in the world in the field of pharmacy by Stanford
University, USA. V Raja Solomon
V Alagarsamy
Dedicated to Education

ISBN: 978-81-5466-147-1

CBS Publishers & Distributors Pvt Ltd

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Other Outstanding CBS Books in Related Subjects
Other Outstanding CBS Books in Related Subjects
Textbook of
Computer Aided
Drug Design
for BPharm Students
As per the latest syllabus prescribed by Pharmacy Council of India
 PCI Syllabus
UNIT 1
Introduction to Drug Discovery and Development
Stages of drug discovery and development

Lead Discovery and Analog Based Drug Design

Rational approaches to lead discovery based on traditional medicine, random screening, non-
random screening, serendipitous drug discovery, lead discovery based on drug metabolism,
lead discovery based on clinical observation.

Analog Based Drug Design

Bioisosterism, Classification, Bioisosteric replacement. Any three case studies

UNIT 2
Quantitative Structure-Activity Relationship (QSAR)
SAR versus QSAR, History and development of QSAR, Types of physicochemical parameters,
experimental and theoretical approaches for the determination of physicochemical parameters
such as partition coefficient, Hammet’s substituent constant and Tafts steric constant. Hansch
analysis, Free Wilson analysis, 3D-QSAR approaches like CoMFA and CoMSIA.

UNIT 3
Molecular Modeling and Virtual Screening Techniques

Virtual Screening Techniques

Drug likeness screening, concept of pharmacophore mapping and pharmacophore based
screening

Molecular Docking
Rigid docking, flexible docking, manual docking, docking based screening. De novo drug
design

UNIT 4
Informatics and Methods in Drug Design
Introduction to bioinformatics, chemo­informatics, ADME databases, chemical, biochemical
and pharmaceutical databases

UNIT 5
Molecular Modeling
Introduction to molecular mechanics and quantum mechanics. energy minimization methods
and conformational analysis, global conformational minima determination
Textbook of
Computer Aided
Drug Design
for BPharm Students
As per the latest syllabus prescribed by Pharmacy Council of India

V Raja Solomon MPharm, PhD

Scientist
Department of Chemistry
University of Saskatchewan
Saskatoon, Saskatchewan, Canada

V Alagarsamy MPharm, PhD, FIC, DOMH

Professor and Principal
MNR College of Pharmacy, Sangareddy
Greater Hyderabad, Telangana
Director
MNR Foundation for Research and Innovations
Sangareddy, Greater Hyderabad, Telangana

CBS Publishers & Distributors Pvt Ltd

New Delhi • Bengaluru • Chennai • Kochi • Kolkata • Lucknow • Mumbai
Hyderabad • Jharkhand • Nagpur • Patna • Pune • Uttarakhand
 Disclaimer
Science and technology are constantly changing
fields. New research and experience broaden
the scope of information and knowledge. The
authors have tried their best in giving information
available to them while preparing the material for
this book. Although all efforts have been made
to ensure optimum accuracy of the material, yet
it is quite possible some errors might have been
left uncorrected. The publisher, the printer and
the authors will not be held responsible for any
inadvertent errors or inaccuracies.

Textbook of
Computer Aided
Drug Design
for BPharm Students
As per the latest syllabus prescribed by Pharmacy Council of India

ISBN: 978-93-5466-147-1

© All rights reserved to CBS Publishers & Distributors Pvt Ltd

First Edition: 2022

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 Preface

T he tremendous response to Prof Alagarsamy’s earlier books (Textbook of Medicinal

Chemistry, Pharmaceutical Chemistry of Natural Products, Pharmaceutical Inorganic
Chemistry, and Pharmaceutical Organic Chemistry) prompted us to write this book covering
all the topics as per the latest syllabus prescribed by Pharmacy Council of India for
BPharm students.
Drug discovery was in place since humans began their existence on the earth, with
records dating back to Charka Samhita and Ebers Papyrus. Initially, it was discovered by
trial and error method by screening a vast array of natural products from plant and animal
extracts. The advancement of knowledge led to the concept of drug-receptor interaction,
target identification, hit and lead development, and screening of small molecules in
vitro and in vivo resulting in the discovery and development of specific, selective and
efficacious drugs.
With the advent of computers and computer-aided drug design (CADD), a paradigm
shift was observed in drug discovery and healthcare. CADD relates principles of
pharmacology, biology, computer science, mathematics, and statistics to analyze and
interpret pharmacological/biological data. This book covers the momentousness of drug
design and knowledge, thereby highlighting its role in advancing modern drug discovery.
The researcher community cannot extricate from any type of large-scale paradigm,
whether it is protein or enzyme structure, that ensures to tackle pharmacological targets.
This book offers an admirable and instructive text on CADD, benefitted by simple to
understand and easy to read layout, uses a rich scholarly text of tremendous intensity,
clarity, and coverage. It emphasizes a number of aspects of CADD to help future
pharmacists, researchers, investigators, and patrons to perform their research with a
greater ease.
For better understanding, the book has been divided into 5 units. Unit 1 gives
an insight into the introduction to drug discovery and development from traditional
medicine to modern concepts like analog-based drug design. Unit 2 focusses the
quantitative structure-activity relationship studies using the Hansch approach, Free
Wilson approach, 3D-QSAR approaches like CoMFA and CoMSIA. Unit 3 integrates
the knowledge of molecular modeling and virtual screening techniques, the concept of
pharmacophore mapping and pharmacophore-based screening, and molecular docking.
Unit 4 explains various informatics techniques and ADME, chemical, biochemical and
pharmaceutical databases used in drug design. Finally, Unit 5 describes the molecular
dynamics simulation approach to investigate the dynamic behaviour of the system and
global conformational minima determination.
We hope that this book will be a good source of information for BPharm students.
Moreover, it will also help researchers involved in drug design related research. We
welcome suggestions and constructive criticism from all corners of the academic
community.
V Raja Solomon
V Alagarsamy
 Acknowledgements

W e wish to place on record our heartfelt thanks to everyone who has made this book
possible, especially our beloved teachers from the first standard to the doctoral
program. We dedicate this book to the hundreds of budding graduates and pharmacy
students, whom we have taught over the years, and our teachers who have encouraged us
to convert our class-notes into textbooks to reach a wide range of academic community.
We are immensely grateful to Prof K Chinnaswamy; Prof B Suresh (Pro-Chancellor,
JSS University, Ex-President, Pharmacy Council of India) and Prof Ramesh K Goyal (Vice
Chancellor, Delhi Pharmaceutical Sciences & Research University), for their constant
support and inspiration extended to us.
We gratefully acknowledge the constant, continuous encouragement and moral
support extended by Shri MN Raju (Chairman, MNR Educational Trust, Hyderabad),
and Mr M Ravi Varma, Vice-Chairman, MNR Educational Trust, Hyderabad, for our
entire academic and research pursuit, is a great motivation for us in taking up this new
challenge.
We thank all the faculty members of the Faculty of Technology, Osmania University,
Hyderabad, for their constant support in all our academic activities.
We express our sincere appreciation to our students, research scholars and friends
especially, Dr MT Sulthana and Dr B Narendhar, for their support in making this book.
We thank CBS Publishers & Distributors, New Delhi, for recognizing us to write this
book. The friendly interaction experienced with the Mr SK Jain, Mr YN Arjuna, and
his team always made us to furnish our inputs and to make this book one of the best.
We thank them wholeheartedly for accepting all views while designing and helping us
publish this book.
Most of all, we thank the ‘Almighty God’ for his endless blessings to make this book
possible.
V Raja Solomon
V Alagarsamy
 Contents

Preface v

UNIT 1
Drug Discovery and Development

Introduction 1

Steps Involved in the Drug Discovery Process 2

Selection of a Disease 3
Selection of Drug Target 3
Bioassay Identification 6
Identification of Lead 7
Isolation and Purification of Lead Compound 15
Determination of the Chemical Structure of Lead Compound 16
Structure–Activity Relationship Determination 16
Pharmacophore Identification 18
Target-Oriented Drug Design 19
Pharmacokinetic Studies in Drug Design 19
Patenting of Drug Molecules 19
Drug Metabolism Studies 20
Designing the Manufacturing Process 25
Clinical Trials Implementation 27
Marketing of Drug 27

Historical Approaches in Drug Discovery 27

Bioisosterism 28
Classification 29

Case Studies 48
Drug Discovery and Development of Pantoprazole as Proton Pump Inhibitors 48
Design and Development of Psychoactive Agents 53
 x Textbook of Computer Aided Drug Design

Development of Quinolone Antibiotics 56

Development of Morphine Analogues 59

Simplification of Drug Dissection 62

Rigidification 67

UNIT 2
Quantitative Structure–Activity Relationship (QSAR)

Introduction 68

Historical Development of QSAR 69

Important Features of SAR 69

Methods for Performing SAR 69

Parameters Governing QSAR 70

Electronic Parameters 70
Steric Parameters 74
Partition Coefficients 75
Biological Relationships 76
Mixed Approach 77

Basic Requirements for QSAR Analysis 78

Classical or 2D QSAR Model Development Procedures 78
Generation of QSAR Models 79
Data Preprocessing 79
Training and Test Datasets 80
Calculation of Molecular Descriptors 80
Feature Selection 81
Classification Based Methods 82
Machine Learning Techniques 83
Software for QSAR Studies and Modeling 84
Validation of Models 85
Statistical Measures Commonly Used in Regression Analysis 87

3D-QSAR Analysis 88
Comparative Molecular Field Analysis (CoMFA) 90
Comparative Molecular Similarity Indices Analysis (CoMSIA) 94

Suggested Readings 97
 Contents xi

UNIT 3
Molecular Modeling and Virtual Screening (VS) Techniques

Pharmacophore Concept and Definition 98

Methodology of Pharmacophore Mapping 100

Diverse Conformation Generation 100
Generation of 3D Pharmacophore 100
Assessment of the Quality of Pharmacophore Hypotheses 102
Validation of the Pharmacophore Model 103

Types of Pharmacophore 104

Ligand-Based Pharmacophore Modeling 105
Structure-Based Pharmacophore Modeling 106
Application of Pharmacophore Models 106

Pharmacophore-Based de novo Design 107

Advantages and Disadvantages of Pharmacophore Modeling 108

Software Tools for Pharmacophore Analysis 108

Structure-Based Design: Docking 109

Concept and Definition of Docking 109
Classification of Docking 109
Definition of Fundamental Terms of Docking 110

Docking Methodologies 115

Rigid Ligand and Rigid Receptor Docking 115
Flexible Ligand and Rigid Receptor Docking 115
Flexible Ligand and Flexible Receptor Docking 116

Virtual Screening: In Silico Screening of Chemical Databases 117

Workflow and Types of VS 118
Successful Application of VS: A Few Case Studies 120
Advantages of VS 121

Suggested Readings 121

UNIT 4
Informatics and Methods in Drug Design

Introduction to Bioinformatics 122

History of Bioinformatics 122
Major Goal of Bioinformatics 122
 xii Textbook of Computer Aided Drug Design

Data of Bioinformatics 123

Retrieval of Data 123
Various Other Goals of Bioinformatics 124
Softwares and Tools 124

Introduction to Cheminformatics 125

Relationship between Chemoinformatics and Bioinformatics 126
Importance of Chemoinformatics 126
Tools Used for Chemoinformatics 127
Applications of Cheminformatics 128
Application of Cheminformatics in Modern Drug Discovery 129
Phases of Drug Discovery and Development --

ADME Databases 131

Biological Databases 133

UNIT 5
Molecular Modeling

Introduction to Molecular Modeling 138

Introduction to Molecular Mechanics and Dynamics 139

Anatomy of a Molecular Mechanics Force-Field 139
Stretching Energy 140
Bending Energy 140
Torsion Energy 142
Nonbonded Energy 143

Introduction to Molecular Dynamics 145

Quantum Mechanics 147
Ab Initio Methods 147
Density Functional Theory Methods 148
Semiempirical Methods 148
Molecular Mechanics or Force Field Methods 148
Combined Quantum Mechanics/Molecular Mechanics Methods 149
Molecular Dynamics (MD) Methods in Combination with Quantum Mechanical Calculations 149
Conformational Analysis and Energy Minimization 149
Conformational Search 150
Minimization of Energy 151

Suggested Readings 153

Index 155

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