Ligand Efficiency Indices for Drug Discovery - 1st Edition - ISBN: 9780124046351, 9780124046825

Ligand Efficiency Indices for Drug Discovery

1st Edition

Towards an Atlas-Guided Paradigm

Authors: Celerino Abad-Zapatero
Paperback ISBN: 9780124046351
eBook ISBN: 9780124046825
Imprint: Academic Press
Published Date: 15th January 2013
Page Count: 178
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Description

Dedication

Acknowledgments

Prologue

The Current Status of Drug Discovery

Introduction

Part 1: The Elements: Data, Variables, Concept, and the Server

Part I. The Elements: Data, Variables, Concept, and the Server

Chapter 1. Structure–Activity Databases for Medicinal Chemistry

1.1 PDB

1.2 PDBBind, MOAD

1.3 ChEMBL

1.4 WOMBAT

1.5 DrugBank

1.6 BindingDB

1.7 PubChem

1.8 Proprietary Databases

1.9 Perspective

1.10 Discussion

Chapter 2. The Variables: Definitions of Ligand Efficiency Indices

2.1 Ligand Efficiencies Based on Free Energy of Binding

2.2 Ligand Efficiencies Based on Physicochemical Properties

2.3 Ligand Efficiencies Based on Atomic Properties

2.4 A Formulation in Polar Coordinates

2.5 Refinements to the definitions of Ligand Efficiency (LE)

2.6 Discussion

Chapter 3. Variables and Data: The AtlasCBS Concept

3.1 The Vastness of Chemical Space

3.2 A Unified Formulation

3.3 The Concept of an Atlas-Like Representation

3.4 AtlasCBS vs. Other Navigation Tools in Medicinal Chemistry

3.5 Discussion

Chapter 4. The AtlasCBS Application

4.1 Basic Elements

4.2 Functionalities

4.3 Discussion

References for Part I

Part II: Conceptual Applications of the AtlasCBS: A New Paradigm

Part II. Conceptual Applications of the AtlasCBS: A New Paradigm

Personal Introduction

Chapter 5. Analysis of the Content of SAR Databases

5.1 Graphical Representation of Lipinski’s Guidelines (Ro5)

5.2 The Territory of Drugs vs. Nondrugs

5.3 Mapping of Bioactive Peptides

5.4 Discussion

Chapter 6. Fragment-Based Strategies

6.1 Analysis of the Content of Fragment Libraries

6.2 Deconvolution of Fragment Efficiencies

6.3 Discussion

Chapter 7. Navigating in Chemicobiological Space

7.1 Trajectories in Chemicobiological Space

7.2 The Search for Optimal Trajectories

7.3 Discussion

References for Part II

Part 3: Exploring CBS: Practical Examples Using the AtlasCBS Server

Part III. Exploring CBS: Practical Examples Using the AtlasCBS Server

Chapter 8. Sightseeing Chemicobiological Space

Introduction: Snapshots, Postcards, Vistas, and Navigational Charts of CBS

8.1 Getting Started: Neuraminidase

8.2 Panoramic View of HIV-LAND: HIV-1 Protease and Reverse Transcriptase

8.3 A Snapshot from Virtual Land: Mapping Calculated Efficiencies

8.4 Wetlands of Cancer—Kinase Inhibitors (Gleevec, Iressa)

8.5 Vistas from Neurotransmission: Acetylcholinesterase

8.6 Glimpses of Receptor Land: G Protein-Coupled Receptors

8.7 FB Lead Generation: Lactic Dehydrogenase A

8.8 A Window into the Future—Prospective Uses of AtlasCBS: Transthyretin

References for Part III

Epilogue

The Road Ahead

Appendix A. Algebraic Derivations

A.1 Derivation of the Relationship Between nBEI and NSEI and Related Variables in the Corresponding Efficiency Planes

Appendix B. Conversion Factors Among Various Ligand Efficiency Indices

B.1 BEI and LE

B.2 LE and NBEI

Key Features

  • Provides a practical and timely discussion of the concepts, ideas, applications and examples of efficiency-driven drug discovery
  • Emphasizes the use of ‘new variables’ and more objective numerical methods to drive quicker and more effective drug discovery
  • Presents the definition of Ligand Efficiency Indices (LEIs) and the corresponding efficiency planes as key concepts to provide a graphical and numerical framework

Readership

Researchers, new professionals and graduate students in medicinal chemistry, drug discovery and pharmaceutical sciences

Table of Contents

Dedication

Acknowledgments

Prologue

The Current Status of Drug Discovery

Introduction

Part 1: The Elements: Data, Variables, Concept, and the Server

Part I. The Elements: Data, Variables, Concept, and the Server

Chapter 1. Structure–Activity Databases for Medicinal Chemistry

1.1 PDB

1.2 PDBBind, MOAD

1.3 ChEMBL

1.4 WOMBAT

1.5 DrugBank

1.6 BindingDB

1.7 PubChem

1.8 Proprietary Databases

1.9 Perspective

1.10 Discussion

Chapter 2. The Variables: Definitions of Ligand Efficiency Indices

2.1 Ligand Efficiencies Based on Free Energy of Binding

2.2 Ligand Efficiencies Based on Physicochemical Properties

2.3 Ligand Efficiencies Based on Atomic Properties

2.4 A Formulation in Polar Coordinates

2.5 Refinements to the definitions of Ligand Efficiency (LE)

2.6 Discussion

Chapter 3. Variables and Data: The AtlasCBS Concept

3.1 The Vastness of Chemical Space

3.2 A Unified Formulation

3.3 The Concept of an Atlas-Like Representation

3.4 AtlasCBS vs. Other Navigation Tools in Medicinal Chemistry

3.5 Discussion

Chapter 4. The AtlasCBS Application

4.1 Basic Elements

4.2 Functionalities

4.3 Discussion

References for Part I

Part II: Conceptual Applications of the AtlasCBS: A New Paradigm

Part II. Conceptual Applications of the AtlasCBS: A New Paradigm

Personal Introduction

Chapter 5. Analysis of the Content of SAR Databases

5.1 Graphical Representation of Lipinski’s Guidelines (Ro5)

5.2 The Territory of Drugs vs. Nondrugs

5.3 Mapping of Bioactive Peptides

5.4 Discussion

Chapter 6. Fragment-Based Strategies

6.1 Analysis of the Content of Fragment Libraries

6.2 Deconvolution of Fragment Efficiencies

6.3 Discussion

Chapter 7. Navigating in Chemicobiological Space

7.1 Trajectories in Chemicobiological Space

7.2 The Search for Optimal Trajectories

7.3 Discussion

References for Part II

Part 3: Exploring CBS: Practical Examples Using the AtlasCBS Server

Part III. Exploring CBS: Practical Examples Using the AtlasCBS Server

Chapter 8. Sightseeing Chemicobiological Space

Introduction: Snapshots, Postcards, Vistas, and Navigational Charts of CBS

8.1 Getting Started: Neuraminidase

8.2 Panoramic View of HIV-LAND: HIV-1 Protease and Reverse Transcriptase

8.3 A Snapshot from Virtual Land: Mapping Calculated Efficiencies

8.4 Wetlands of Cancer—Kinase Inhibitors (Gleevec, Iressa)

8.5 Vistas from Neurotransmission: Acetylcholinesterase

8.6 Glimpses of Receptor Land: G Protein-Coupled Receptors

8.7 FB Lead Generation: Lactic Dehydrogenase A

8.8 A Window into the Future—Prospective Uses of AtlasCBS: Transthyretin

References for Part III

Epilogue

The Road Ahead

Appendix A. Algebraic Derivations

A.1 Derivation of the Relationship Between nBEI and NSEI and Related Variables in the Corresponding Efficiency Planes

Appendix B. Conversion Factors Among Various Ligand Efficiency Indices

B.1 BEI and LE

B.2 LE and NBEI

Details

No. of pages:
178
Language:
English
Copyright:
© Academic Press 2013
Published:
Imprint:
Academic Press
eBook ISBN:
9780124046825
Paperback ISBN:
9780124046351

About the Author

Celerino Abad-Zapatero

Affiliations and Expertise

PhD, Adjunct Professor to the Graduate Faculty, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL

Reviews

"For those interested in a fresh interpretation of the utility of ligand efficiency indexes for drug discovery, this book serves as a nice introduction to a more modern, graphical approach to drug lead identification."--Doody.com, August 16, 2013
"Abad-Zapatero presents a novel approach to drug discovery that is based on the notion that a change of variables is necessary. The algebraic framework he proposes combines the affinity between ligands and targets with the physico-chemical properties of the ligands to construct a set of novel variables that can map chemico-biological space (CBS) and optimize the drug-discovery process."--Reference and Research Book News, August 2013