Structure-based Design of Drugs and Other Bioactive Molecules E-Book

Arun K. Ghosh

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 690

Veröffentlichungsjahr: 2014

Beschreibung

Drug design is a complex, challenging and innovative research area. Structure-based molecular design has transformed the drug discovery approach in modern medicine. Traditionally, focus has been placed on computational, structural or synthetic methods only in isolation. This one-of-akind guide integrates all three skill sets for a complete picture of contemporary structure-based design.

This practical approach provides the tools to develop a high-affinity ligand with drug-like properties for a given drug target for which a high-resolution structure exists. The authors use numerous examples of recently developed drugs to present "best practice" methods in structurebased drug design with both newcomers and practicing researchers in mind. By way of a carefully balanced mix of theoretical background and case studies from medicinal chemistry applications, readers will quickly and efficiently master the basic skills of successful drug design.

This book is aimed at new and active medicinal chemists, biochemists, pharmacologists, natural product chemists and those working in drug discovery in the pharmaceutical industry. It is highly recommended as a desk reference to guide students in medicinal and chemical sciences as well as to aid researchers engaged in drug design today.

Leseprobe

CONTENTS

Cover

Related Titles

Title Page

Copyright

Preface

Chapter 1: From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design

1.1 Introduction

1.2 Drug Discovery During 1928–1980

1.3 The Beginning of Structure-Based Drug Design

1.4 Conclusions

References

Part One: Concepts, Tools, Ligands, and Scaffolds for Structure-Based Design of Inhibitors

Chapter 2: Design of Inhibitors of Aspartic Acid Proteases

2.1 Introduction

2.2 Design of Peptidomimetic Inhibitors of Aspartic Acid Proteases

2.3 Design of Statine-Based Inhibitors

2.4 Design of Hydroxyethylene Isostere-Based Inhibitors

2.5 Design of Inhibitors with Hydroxyethylamine Isosteres

2.6 Design of (Hydroxyethyl)urea-Based Inhibitors

2.7 (Hydroxyethyl)sulfonamide-Based Inhibitors

2.8 Design of Heterocyclic/Nonpeptidomimetic Aspartic Acid Protease Inhibitors

References

Chapter 3: Design of Serine Protease Inhibitors

3.1 Introduction

3.2 Catalytic Mechanism of Serine Protease

3.3 Types of Serine Protease Inhibitors

3.4 Halomethyl Ketone-Based Inhibitors

3.5 Diphenyl Phosphonate-Based Inhibitors

3.6 Trifluoromethyl Ketone Based Inhibitors

3.7 Peptidyl Boronic Acid-Based Inhibitors

3.8 Peptidyl α-Ketoamide- and α-Ketoheterocycle-Based Inhibitors

3.9 Design of Serine Protease Inhibitors Based Upon Heterocycles

3.10 Reversible/Noncovalent Inhibitors

3.11 Conclusions

References

Chapter 4: Design of Proteasome Inhibitors

4.1 Introduction

4.2 Catalytic Mechanism of 20S Proteasome

4.3 Proteasome Inhibitors

4.4 Synthesis of β-Lactone Scaffold

4.5 Synthesis of Epoxy Ketone Scaffold

4.6 Conclusions

References

Chapter 5: Design of Cysteine Protease Inhibitors

5.1 Introduction

5.2 Development of Cysteine Protease Inhibitors with Michael Acceptors

5.3 Design of Noncovalent Cysteine Protease Inhibitors

5.4 Conclusions

References

Chapter 6: Design of Metalloprotease Inhibitors

6.1 Introduction

6.2 Design of Matrix Metalloprotease Inhibitors

6.3 Design of Inhibitors of Tumor Necrosis Factor-α-Converting Enzymes

6.4 Conclusions

References

Chapter 7: Structure-Based Design of Protein Kinase Inhibitors

7.1 Introduction

7.2 Active Site of Protein Kinases

7.3 Catalytic Mechanism of Protein Kinases

7.4 Design Strategy for Protein Kinase Inhibitors

7.5 Nature of Kinase Inhibitors Based upon Binding

References

Chapter 8: Protein X-Ray Crystallography in Structure-Based Drug Design

8.1 Introduction

8.2 Protein Expression and Purification

8.3 Synchrotron Radiation

8.4 Structural Biology in Fragment-Based Drug Design

8.5 Selected Examples of Fragment-Based Studies

8.6 Conclusions

References

Chapter 9: Structure-Based Design Strategies for Targeting G-Protein-Coupled Receptors (GPCRs)

9.1 Introduction

9.2 High-Resolution Structures of GPCRs

9.3 Virtual Screening Applied to the β2-Adrenergic Receptor

9.4 Structure-Based Design of Adenosine A2A Receptor Antagonists

9.5 Structure-Guided Design of CCR5 Antagonists

References

Part Two: Structure-Based Design of FDA-Approved Inhibitor Drugs and Drugs Undergoing Clinical Development

Chapter 10: Angiotensin-Converting Enzyme Inhibitors for the Treatment of Hypertension: Design and Discovery of Captopril

10.1 Introduction

10.2 Design of Captopril: the First Clinically Approved Angiotensin-Converting Enzyme Inhibitor

10.3 Structure of Angiotensin-Converting Enzyme

10.4 Design of ACE Inhibitors Containing a Carboxylate as Zinc Binding Group

10.5 ACE Inhibitors Bearing Phosphorus-Based Zinc Binding Groups

10.6 Conclusions

References

Chapter 11: HIV-1 Protease Inhibitors for the Treatment of HIV Infection and AIDS: Design of Saquinavir, Indinavir, and Darunavir

11.1 Introduction

11.2 Structure of HIV Protease and Design of Peptidomimetic Inhibitors Containing Transition-State Isosteres

11.3 Saquinavir: the First Clinically Approved HIV-1 Protease Inhibitor

11.4 Indinavir: an HIV Protease Inhibitor Containing the Hydroxyethylene Transition-State Isostere

11.5 Design and Development of Darunavir

11.6 Design of Cyclic Ether Templates in Drug Discovery

11.7 Investigation of Cyclic Sulfones as P2 Ligands

11.8 Design of Bis-tetrahydrofuran and Other Bicyclic P2 Ligands

11.9 The “Backbone Binding Concept” to Combat Drug Resistance: Inhibitor Design Strategy Promoting Extensive Backbone Hydrogen Bonding from S2 to S2′ Subsites

11.10 Design of Darunavir and Other Inhibitors with Clinical Potential

11.11 Conclusions

References

Chapter 12: Protein Kinase Inhibitor Drugs for Targeted Cancer Therapy: Design and Discovery of Imatinib, Nilotinib, Bafetinib, and Dasatinib

12.1 Introduction

12.2 Evolution of Kinase Inhibitors as Anticancer Agents

12.3 The Discovery of Imatinib

12.4 Imatinib: the Structural Basis of Selectivity

12.5 Pharmacological Profile and Clinical Development

12.6 Imatinib Resistance

12.7 Different Strategies for Combating Drug Resistance

12.8 Conclusions

References

Chapter 13: NS3/4A Serine Protease Inhibitors for the Treatment of HCV: Design and Discovery of Boceprevir and Telaprevir

13.1 Introduction

13.2 NS3/4A Structure

13.3 Mechanism of Peptide Hydrolysis by NS3/4A Serine Protease

13.4 Development of Mechanism-Based Inhibitors

13.5 Strategies for the Development of HCV NS3/4A Protease Inhibitors

13.6 Initial Studies toward the Development of Boceprevir

13.7 Reduction of Peptidic Character

13.8 Optimization of P2 Interactions

13.9 Truncation Strategy: the Path to Discovery of Boceprevir

13.10 The Discovery of Telaprevir

13.11 Simultaneous P1, P1′, P2, P3, and P4 Optimization Strategy: the Path to Discovery of Telaprevir

13.12 Conclusions

References

Chapter 14: Proteasome Inhibitors for the Treatment of Relapsed Multiple Myeloma: Design and Discovery of Bortezomib and Carfilzomib

14.1 Introduction

14.2 Discovery of Bortezomib

14.3 Discovery of Carfilzomib

14.4 Conclusions

References

Chapter 15: Development of Direct Thrombin Inhibitor, Dabigatran Etexilate, as an Anticoagulant Drug

15.1 Introduction

15.2 Coagulation Cascade and Anticoagulant Drugs

15.3 Anticoagulant Therapies

15.4 Structure of Thrombin

15.5 The Discovery of Dabigatran Etexilate

15.6 Conclusions

References

Chapter 16: Non-Nucleoside HIV Reverse Transcriptase Inhibitors for the Treatment of HIV/AIDS: Design and Development of Etravirine and Rilpivirine

16.1 Introduction

16.2 Structure of the HIV Reverse Transcriptase

16.3 Discovery of Etravirine and Rilpivirine

16.4 Conclusions

References

Chapter 17: Renin Inhibitor for the Treatment of Hypertension: Design and Discovery of Aliskiren

17.1 Introduction

17.2 Structure of Renin

17.3 Peptidic Inhibitors with Transition-State Isosteres

17.4 Peptidomimetic Inhibitors

17.5 Design of Peptidomimetic Inhibitors

17.6 Biological Properties of Aliskiren

17.7 Conclusions

References

Chapter 18: Neuraminidase Inhibitors for the Treatment of Influenza: Design and Discovery of Zanamivir and Oseltamivir

18.1 Introduction

18.2 Discovery of Zanamivir

18.3 Discovery of Oseltamivir

18.4 Conclusions

References

Chapter 19: Carbonic Anhydrase Inhibitors for the Treatment of Glaucoma: Design and Discovery of Dorzolamide

19.1 Introduction

19.2 Design and Discovery of Dorzolamide

19.3 Conclusions

References

Chapter 20: β-Secretase Inhibitors for the Treatment of Alzheimer's Disease: Preclinical and Clinical Inhibitors

20.1 Introduction

20.2 β-Secretase and Its X-Ray Structure

20.3 Development of First Peptidomimetic BACE Inhibitors

20.4 X-Ray Structure of Inhibitor-Bound BACE1

20.5 Design and Development of Selective Inhibitors

20.6 Design of Small-Molecule Inhibitors with Clinical Potential

20.7 GRL-8234 (18) Rescued Cognitive Decline in AD Mice

20.8 BACE1 Inhibitors for Clinical Development

20.9 Conclusions

References

Index

End User License Agreement

List of Tables

Table 1.1

Table 12.1

Table 12.2

Table 14.1

Table 14.2

Table 14.3

Table 15.1

Table 15.2

Table 16.1

Table 16.2

Table 17.1

Table 17.2

Table 17.3

Table 17.4

Table 17.5

Table 17.6

Table 17.7

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 1.4

Figure 1.5

Figure 1.6

Figure 1.7

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 2.8

Figure 2.9

Figure 2.10

Figure 2.11

Figure 2.12

Figure 2.13

Figure 2.14

Figure 2.15

Figure 2.16

Figure 2.17

Figure 2.18

Figure 2.19

Figure 2.20

Figure 2.21

Figure 2.22

Figure 2.23

Figure 2.24

Figure 2.25

Figure 2.26

Figure 2.27

Figure 2.28

Figure 2.29

Figure 2.30

Figure 2.31

Figure 2.32

Figure 2.33

Figure 2.34

Figure 2.35

Figure 2.36

Figure 2.37

Figure 2.38

Figure 2.39

Figure 2.40

Figure 2.41

Figure 2.42

Figure 2.43

Figure 2.44

Figure 2.45

Figure 2.46

Figure 2.47

Figure 2.48

Figure 2.49

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 3.7

Figure 3.8

Figure 3.9

Figure 3.10

Figure 3.11

Figure 3.12

Figure 3.13

Figure 3.14

Figure 3.15

Figure 3.16

Figure 3.17

Figure 3.18

Figure 3.19

Figure 3.20

Figure 3.21

Figure 3.22

Figure 3.23

Figure 3.24

Figure 3.25

Figure 3.26

Figure 3.27

Figure 3.28

Figure 3.29

Figure 3.30

Figure 3.31

Figure 3.32

Figure 3.33

Figure 3.34

Figure 3.35

Figure 3.36

Figure 3.37

Figure 3.38

Figure 3.39

Figure 3.40

Figure 3.41

Figure 3.42

Figure 3.43

Figure 3.44

Figure 3.45

Figure 3.46

Figure 3.47

Figure 3.48

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 4.8

Figure 4.9

Figure 4.10

Figure 4.11

Figure 4.12

Figure 4.13

Figure 4.14

Figure 4.15

Figure 4.16

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.5

Figure 5.6

Figure 5.7

Figure 5.8

Figure 5.9

Figure 5.10

Figure 5.11

Figure 5.12

Figure 5.13

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 6.8

Figure 6.9

Figure 6.10

Figure 6.11

Figure 7.1

Figure 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Figure 7.7

Figure 7.8

Figure 7.9

Figure 7.10

Figure 7.11

Figure 7.12

Figure 7.13

Figure 7.14

Figure 7.15

Figure 7.16

Figure 7.17

Figure 7.18

Figure 7.19

Figure 7.20

Figure 7.21

Figure 7.22

Figure 7.23

Figure 7.24

Figure 7.25

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.5

Figure 8.6

Figure 8.7

Figure 8.8

Figure 8.9

Figure 8.10

Figure 8.11

Figure 8.12

Figure 8.13

Figure 8.14

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 9.5

Figure 9.6

Figure 9.7

Figure 9.8

Figure 9.9

Figure 9.10

Figure 9.11

Figure 9.12

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 10.12

Figure 10.13

Figure 10.14

Figure 10.15

Figure 10.16

Figure 10.17

Figure 10.18

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 11.6

Figure 11.7

Figure 11.8

Figure 11.9

Figure 11.10

Figure 11.11

Figure 11.12

Figure 11.13

Figure 11.14

Figure 11.15

Figure 11.16

Figure 11.17

Figure 11.18

Figure 11.19

Figure 11.20

Figure 11.21

Figure 11.22

Figure 11.23

Figure 11.24

Figure 11.25

Figure 11.26

Figure 11.27

Figure 11.28

Figure 12.1

Figure 12.2

Figure 12.3

Figure 12.4

Figure 12.5

Figure 12.6

Figure 12.7

Figure 12.8

Figure 12.9

Figure 12.10

Figure 12.11

Figure 12.12

Figure 12.13

Figure 13.1

Figure 13.2

Figure 13.3

Figure 13.4

Figure 13.5

Figure 13.6

Figure 13.7

Figure 13.8

Figure 13.9

Figure 13.10

Figure 13.11

Figure 13.12

Figure 13.13

Figure 13.14

Figure 13.15

Figure 13.16

Figure 13.17

Figure 13.18

Figure 13.19

Figure 13.20

Figure 13.21

Figure 14.1

Figure 14.2

Figure 14.3

Figure 14.4

Figure 14.5

Figure 14.6

Figure 14.7

Figure 14.8

Figure 14.9

Figure 15.1

Figure 15.2

Figure 15.3

Figure 15.4

Figure 15.5

Figure 15.6

Figure 15.7

Figure 15.8

Figure 15.9

Figure 15.10

Figure 15.11

Figure 15.12

Figure 15.13

Figure 15.14

Figure 15.15

Figure 16.1

Figure 16.2

Figure 16.3

Figure 16.4

Figure 16.5

Figure 16.6

Figure 16.7

Figure 16.8

Figure 16.9

Figure 16.10

Figure 16.11

Figure 16.12

Figure 16.13

Figure 16.14

Figure 16.15

Figure 17.1

Figure 17.2

Figure 17.3

Figure 17.4

Figure 17.5

Figure 17.6

Figure 17.7

Figure 17.8

Figure 17.9

Figure 17.10

Figure 17.11

Figure 17.12

Figure 17.13

Figure 17.14

Figure 17.15

Figure 17.16

Figure 18.1

Figure 18.2

Figure 18.3

Figure 18.4

Figure 18.5

Figure 18.6

Figure 18.7

Figure 18.8

Figure 18.9

Figure 18.10

Figure 18.11

Figure 18.12

Figure 19.1

Figure 19.2

Figure 19.3

Figure 19.4

Figure 19.5

Figure 19.6

Figure 19.7

Figure 19.8

Figure 20.1

Figure 20.2

Figure 20.3

Figure 20.4

Figure 20.5

Figure 20.6

Figure 20.7

Figure 20.8

Figure 20.9

Figure 20.10

Figure 20.11

Figure 20.12

Figure 20.13

Figure 20.14

Figure 20.15

Figure 20.16

Figure 20.17

Figure 20.18

Figure 20.19

Figure 20.20

Figure 20.21

Guide

Cover

Table of Contents

Preface

Part 1

Chapter 1

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Structure-based Design of Drugs and Other Bioactive Molecules

Tools and Strategies

Arun K. Ghosh

Sandra Gemma

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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Preface

As our knowledge of the structure and function of proteins has expanded, new techniques employing this knowledge as the basis for drug design and discovery have emerged and taken the lead. The impact of structure-based design strategies has been dramatic and far-reaching, resulting in the discovery and development of numerous FDA-approved drugs, many of which are first-in-class medicines. Major advancements in molecular biology and technology have led to in-depth structural knowledge of new disease-relevant target enzymes. Improvements in X-ray crystallographic techniques have created an important database and enabled a better understanding of the role of enzyme–ligand interactions. Progress in computer analysis has also played a vital role in advancing structure-based design capabilities since the 1980s. Today, structure-based design has become one of the most innovative and dynamic areas of drug design and discovery.

Over the years, the Ghosh laboratories have gained extensive experience with structure-based design. The development of conceptually novel inhibitors against HIV-1 protease for the treatment of HIV/AIDS has been an important area of research that led to the design and discovery of darunavir, the first FDA-approved treatment for drug-resistant HIV/AIDS. Structure-based design of β-secretase 1 (BACE1) inhibitors for the treatment of Alzheimer's disease also started in the Ghosh laboratories with the design and synthesis of the first substrate-based transition-state inhibitors, determination of the first X-ray crystal structure of inhibitor-bound BACE1, followed by design and development of potent and selective inhibitors with clinical potential. The Ghosh laboratories have also led the design of coronavirus 3CLPro and PLpro inhibitors for possible treatment of SARS/Mers and the design of methyltransferase inhibitors for possible treatment of dengue virus infection. Our experience in structure-based design in these diverse areas is detailed within this book.

A significant body of structure-based design work for many approved therapeutic drugs and preclinical and clinical candidates has been reported by numerous academic and pharmaceutical scientists. This work has led to the development of tools, strategies, and concepts that aid the process of structure-based design. A substantial part of this work has been an integral part of the lecture notes of one of the authors for teaching fundamentals and concepts of drug discovery and design to students at Purdue University. During these research and teaching endeavors, an important need for writing this book was recognized. Although there are many elegant reports of the structure-based design of therapeutic drugs that span three decades now, a systematic presentation of the evolution of the field, principles, and applications had not yet been compiled. The materials of this treatise are organized with these objectives in mind. This book covers a critical overview of the history of structure-based drug design, an analysis of the underlying principles, and an up-to-date description of the X-ray techniques and methods that led to the structure determination of many important biomolecules. The book also highlights the structure-based design and drug development process covering a broad array of FDA-approved medications. The reader will gain a sense of how a drug interacts with its biological target at the molecular level and how the drug–target interactions can be optimized in order to increase affinity with desired physicochemical and drug-like properties. Furthermore, the reader will gain knowledge of how other factors such as in vivo efficacy and physicochemical and pharmacokinetic parameters need to be optimized in order to convert a lead compound into a clinical drug structure.

Chapter 1 provides a historical perspective of drug discovery encompassing discovery through serendipity and natural product screening to the evolution of the field of structure-based design of today's medicines. Chapters 2–7 outline general principles for design of enzyme inhibitors covering aspartic acid proteases, serine proteases, cysteine proteases, metalloproteases, threonine proteases, and protein kinases. These chapters highlight the key protein–ligand interactions and evolution of ligands, scaffolds, and templates to aid molecular design of lead inhibitors and their optimization. These chapters also cover the synthesis of a selection of ligands, templates, and isosteres generally utilized for structure-based design. Chapter 8 reviews recent progress in gaining high-resolution structural knowledge of biologically relevant proteins and G-protein-coupled receptors (GPCRs), particularly the methods of X-ray crystallography and their application in lead discovery. Chapter 9 covers recent developments in the structure-based design of novel ligands for GPCRs, an exciting new dimension for GPCR research.

Chapters 10–20 cover an array of recently FDA-approved drugs developed by utilizing structure-based design strategies. These chapters highlight the mechanism of action associated with each drug class, in-depth structural analysis of protein–ligand interactions, structural design, and optimization of ligand binding to protein structures. Chapter 10 is devoted to the design of the first ACE inhibitor, captopril, which marks the beginning of structure-based design. Chapters 11–19 cover the design and development of HIV-1 protease inhibitors such as saquinavir, indinavir, and darunavir (Chapter 11); kinase inhibitor drugs imatinib, nilotinib, and dasatinib (Chapter 12); NS3/4A serine protease inhibitor drugs boceprevir and telaprevir for the treatment of HCV (Chapter 13); proteasome inhibitor drugs bortezomib and carfilzomib for the treatment of relapsed multiple myeloma (Chapter 14); development of direct thrombin inhibitor dabigatran etexilate (Chapter 15); non-nucleoside HIV reverse-transcriptase inhibitors etravirine and rilpivirine (Chapter 16); development of renin inhibitor aliskiren (Chapter 17); neuraminidase inhibitors zanamivir and oseltamivir for the treatment of influenza (Chapter 18); and carbonic anhydrase inhibitor dorzolamide (Chapter 19) for the treatment of glaucoma. The last chapter outlines the development of β-secretase inhibitors that are at various stages of preclinical and clinical development for possible treatment of Alzheimer's disease.

Overall, this book will greatly enhance the readers' understanding of structure-based design and drug discovery, its potential, underlying principles, feasibility, and limitations. We believe that the book will be an excellent resource for new and practicing medicinal chemists, biologists, biochemists, and pharmacologists who are interested in working in the field of molecular design for discovery and development of human medicine. Structure-based design has a critical role in today's drug design and discovery, and it will continue to play a very prominent role in drug design and medicinal chemistry endeavors throughout the twenty-first century. We hope that the book will be helpful to researchers involved in drug discovery and the pursuit of knowledge in structure-based design and related areas.

We gratefully acknowledge the National Institutes of Health for financial support of our research work.

We very much enjoyed working with Drs. Frank Weinreich and Lesley Belfit and the Wiley-VCH editorial team. We sincerely appreciate their help and support throughout this project. We would like to thank Dr. Hiroaki Mitsuya, Dr. Jordan Tang and Dr. Irene Weber for longstanding and productive research collaboration. We would like to express our appreciation and thanks to our research colleagues from Purdue University, Dr. Venkateswararao Kalapala, Dr. Navanth Gavande, Ms. Heather Osswald, Mr. Anindya Sarkar, Ms. Kelsey Cantwell and Mr. Anthony Tomaine for their invaluable help with proofreading and reviewing of this work. We wish to convey special thanks and appreciation to Dr. Jody Ghosh for her help and support and Mrs. JoAnna Hadley for her help with the manuscript preparation and organization. Finally, we wish to thank our families for their love, support, and inspiration.

Arun K. Ghosh

Purdue University

Sandra Gemma

Purdue University & University of Siena

1From Traditional Medicine to Modern Drugs: Historical Perspective of Structure-Based Drug Design

1.1 Introduction

The drug design and discovery process of today is a highly interdisciplinary research endeavor [1–3]. Advances in molecular biology, synthetic chemistry, and pharmacology, as well as technological breakthroughs in X-ray crystallography and computational methods have brought dramatic changes to medicinal chemistry practices during the late twentieth century. Drug design efforts based upon the three-dimensional structure of a target enzyme have become the hallmark of modern molecular design strategies. This structure-based design approach has revolutionized the practice of medicinal chemistry and recast the preclinical drug discovery process. Many of the FDA-approved drugs have evolved through structure-based design strategies. By 2012, as many as 35 newly approved drugs have emanated from structure-based design. The post-genomic era holds huge promise for the advancement of structure-based design of drugs for new therapies. Human genome sequencing has now revealed that there are an estimated 20,000–25,000 protein-coding human genes, and each gene can code for one protein. These proteins are responsible for carrying out all the cellular functions in the human body. These proteins can also be involved in disease pathologies, providing unique opportunities and challenges for structure-based design of new drugs. It may be appropriate to review briefly how the first half of the twentieth century was shaped and enriched by a number of seminal discoveries and the advent of new technologies, all of which left an important imprint on today's drug discovery and medicinal chemistry. A number of previous reviews have provided some insight [4,5].