Ligand Efficiency Indices for Drug Discovery

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