Preface.

A Personal Foreword.

I Introduction.

1 A Fresh Look at Molecular Structure and Properties (Bernard Testa, Giulio Vistoli, and Alessandro Pedretti).

1.1 Introduction.

1.2 Core Features: The Molecular “Genotype”.

1.3 Observable and Computable Properties: The Molecular “Phenotype”.

1.4 Molecular Properties and their Adaptability: The Property Space of Molecular Entities.

1.5 Conclusions.

2 Physicochemical Properties in Drug Profi ling (Han van de Waterbeemd).

2.1 Introduction.

2.2 Physicochemical Properties and Pharmacokinetics.

2.3 Dissolution and Solubility.

2.4 Ionization (pKa).

2.5 Molecular Size and Shape.

2.6 H-bonding.

2.7 Lipophilicity.

2.8 Permeability.

2.9 Amphiphilicity.

2.10 Drug-like Properties.

2.11 Computation versus Measurement of Physicochemical Properties.

2.12 Outlook.

II Electronic Properties and H-Bonding.

3 Drug Ionization and Physicochemical Profi ling (Alex Avdeef).

3.1 Introduction.

3.2 Accurate Determination of Ionization Constants.

3.3 “Octanol” and “Membrane” pKa in Partition Coefficients Measurement.

3.4 “Gibbs” and Other “Apparent” pKa in Solubility Measurement.

3.5 “Flux” and other “Apparent” pKa in Permeability Measurement.

3.6 Conclusions.

4 Electrotopological State Indices (Ovidiu Ivanciuc).

4.1 Introduction.

4.2 E-state Indices.

4.3 Application of E-State Indices in Medicinal Chemistry.

4.4 Conclusions and Outlook.

5 Polar Surface Area (Peter Ertl).

5.1 Introduction.

5.2 Application of PSA for Prediction of Drug Transport Properties.

5.3 Application of PSA in Virtual Screening.

5.4 Calculation of PSA.

5.5 Correlation of PSA with other Molecular Descriptors.

5.6 Conclusions.

6 H-bonding Parameterization in Quantitative Structure–Activity Relationships and Drug Design (Oleg Raevsky).

6.1 Introduction.

6.2 Two-dimensional H-bond Descriptors.

6.3 Three-dimensional H-bond Descriptors.

6.4 Application of H-bond Descriptors in QSAR Studies and Drug Design.

6.5 Conclusions.

III Conformations.

7 Three-dimensional Structure Generation (Jens Sadowski).

7.1 Introduction.

7.2 Problem Description.

7.3 Concepts.

7.4 Practical Aspects.

7.5 Conclusions.

8 Exploiting Ligand Conformations in Drug Design (Jonas Boström and Andrew Grant).

8.1 Introduction.

8.2 Generating Relevant Conformational Ensembles.

8.3 Using Conformational Effects in Drug Design.

8.4 Conclusions.

9 Conformational Analysis of Drugs by Nuclear Magnetic Resonance Spectroscopy (Burkhard Luy, Andreas Frank, and Horst Kessler).

9.1 Introduction.

9.2 NMR Parameters for Conformational Analysis.

9.3 Conformation Bound to the Receptor.

9.4 Refi nement of Conformations by Computational Methods.

IV Solubility.

10 Drug Solubility in Water and Dimethylsulfoxide (Christopher Lipinski).

10.1 Introduction.

10.2 Water Solubility.

10.3 Early Discovery Water Solubility and Biological Testing.

10.4 Water Solubility Measurement Technology.

10.5 Compound Ionization Properties.

10.6 Compound Solid-state Properties.

10.7 DMSO Solubility.

10.8 Conclusions.

11 Challenge of Drug Solubility Prediction (Andreas Klamt and Brian J Smith).

11.1 Importance of Aqueous Drug Solubility.

11.2 Thermodynamic States Relevant for Drug Solubility.

11.3 Prediction of ΔG fus.

11.4 Prediction of Liquid Solubility with COSMO-RS.

11.5 Prediction of Liquid Solubility with Molecular Dynamics (MD) and Monte Carlo (MC) Methods.

11.6 Group–Group Interaction Methods.

11.7 Nonlinear Character of Log Sw.

11.8 QSPRs.

11.9 Experimental Solubility Datasets.

11.10 Atom Contribution Methods, Electrotopological State (E-state) Indices and GCMs.

11.11 Three-dimensional Geometry-based Models.

11.12 Conclusions and Outlook.

V Lipophilicity.

12 Lipophilicity: Chemical Nature and Biological Relevance (Giulia Caron and Giuseppe Ermondi).

12.1 Chemical Nature of Lipophilicity.

12.2 Biological Relevance of Lipophilicity.

12.3 Conclusions.

13 Chromatographic Approaches for Measuring Log P (Sophie Martel, Davy Guillarme, Yveline Henchoz, Alexandra Galland, Jean-Luc Veuthey, Serge Rudaz, and Pierre-Alain Carrupt).

13.1 Introduction.

13.2 Lipophilicity Measurements by RPLC: Isocratic Conditions.

13.3 Lipophilicity Measurements by RPLC: Gradient Approaches.

13.4 Lipophilicity Measurements by Capillary Electrophoresis (CE).

13.5 Supplementary Material.

14 Prediction of Log P with Substructure-based Methods (Raimund Mannhold and Claude Ostermann).

14.1 Introduction.

14.2 Fragmental Methods.

14.3 Atom-based Methods.

14.4 Predictive Power of Substructure-based Approaches.

15 Prediction of Log P with Property-based Methods (Igor V. Tetko and Gennadiy I. Poda).

15.1 Introduction.

15.2 Methods Based on 3D Structure Representation.

15.3 Methods Based on Topological Descriptors.

15.4 Prediction Power of Property-based Approaches.

15.5 Conclusions.

16 The Good, the Bad and the Ugly of Distribution Coeffi cients: Current Status, Views and Outlook (Franco Lombardo, Bernard Faller, Marina Shalaeva, Igor Tetko, and Suzanne Tilton).

16.1 Log D and Log P.

16.2 Issues and Automation in the Determination of Log D.

16.3 pH-partition Theory and Ion-pairing.

16.4 Computational Approaches.

16.5 Some Concluding Remarks: The Good, the Bad and the Ugly.

VI Drug- and Lead-likeness.

17 Properties Guiding Drug- and Lead-likeness (Sorel Muresan and Jens Sadowski).

17.1 Introduction.

17.2 Properties of Leads and Drugs.

17.3 Drug-likeness as a Classifi cation Problem.

17.4 Application Example: Compound Acquisition.

17.5 Conclusions.

Index.