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Mannhold Methods and Principles in Medicinal Chemistry Molecular Drug Properties Edited by Raimund Mannhold Methods and Principles in Medicinal Chemistry Edited by R. Mannhold, H. Kubinyi, G. Folkers Editorial Board H. Timmerman, J. Vacca, H. van de Waterbeemd, T. Wieland Previous Volumes of this Series: G. Cruciani (ed.) T. Langer, R. D. Hofmann (eds.) Molecular Interaction Fields Pharmacophores and Vol. 27 Pharmacophore Searches 2006, ISBN 978-3-527-31087-6 Vol. 32 2006, ISBN 978-3-527-31250-4 M. Hamacher, K. Marcus, K. Stühler, A. van Hall, B. Warscheid, H. E. Meyer (eds.) E. Francotte, W. Lindner (eds.) Proteomics in Drug Research Chirality in Drug Research Vol. 28 Vol. 33 2006, ISBN 978-3-527-31226-9 2006, ISBN 978-3-527-31076-0 D. J. Triggle, M. Gopalakrishnan, W. Jahnke, D. A. Erlanson (eds.) D. Rampe, W. Zheng (eds.) Fragment-based Approaches Voltage-Gated Ion Channels in Drug Discovery as Drug Targets Vol. 34 Vol. 29 2006, ISBN 978-3-527-31291-7 2006, ISBN 978-3-527-31258-0 D. Rognan (ed.) J. Hüser (ed.) Ligand Design for G High-Throughput Screening Protein-coupled Receptors in Drug Discovery Vol. 30 Vol. 35 2006, ISBN 978-3-527-31284-9 2006, ISBN 978-3-527-31283-2 D. A. Smith, H. van de Waterbeemd, K. Wanner, G. Höfner (eds.) D. K. Walker Mass Spectrometry in Pharmacokinetics and Medicinal Chemistry Metabolism in Drug Design, Vol. 36 2nd Ed. 2007, ISBN 978-3-527-31456-0 Vol. 31 2006, ISBN 978-3-527-31368-6 Molecular Drug Properties Measurement and Prediction Edited by Raimund Mannhold Series Editors All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and Prof. Dr. Raimund Mannhold publisher do not warrant the information contained Molecular Drug Research Group in these books, including this book, to be free of Heinrich-Heine-Universität errors. Readers are advised to keep in mind that Universitätsstrasse 1 statements, data, illustrations, procedural details or 40225 Düsseldorf other items may inadvertently be inaccurate. Germany [email protected] Library of Congress Card No.: applied for Prof. Dr. Hugo Kubinyi Donnersbergstrasse 9 British Library Cataloguing-in-Publication Data 67256 Weisenheim am Sand A catalogue record for this book is available from Germany the British Library. [email protected] Bibliographic information published by Prof. Dr. Gerd Folkers the Deutsche Nationalbibliothek Collegium Helveticum Die Deutsche Nationalbibliothek lists this STW/ETH Zurich publication in the Deutsche Nationalbibliografi e; 8092 Zurich detailed bibliographic data are available in the Switzerland Internet at <http://dnb.d-nb.de>. [email protected] © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Volume Editor All rights reserved (including those of translation Prof. Dr. Raimund Mannhold into other languages). No part of this book may be Molecular Drug Research Group reproduced in any form – by photoprinting, Heinrich-Heine-Universität microfi lm, or any other means – nor transmitted or Universitätsstrasse 1 translated into a machine language without written 40225 Düsseldorf permission from the publishers. Registered names, Germany trademarks, etc. used in this book, even when not [email protected] specifi cally marked as such, are not to be considered unprotected by law. Cover Illustration Composition SNP Best-set Typesetter Ltd., Hong Kong Molecular lipophilicity potentials for an extended, more lipophilic and a folded, less lipophilic Printing Betz-Druck GmbH, Darmstadt conformer of verapamil are shown (∆logPMLP = 0.6). Violet regions: higher lipophilicity; blue regions: Bookbinding Litges & Dopf GmbH, Heppenheim medium lipophilicity; yellow regions: weakly polar; red regions: strongly polar (Preparation of this Cover Design Grafi k-Design Schulz, Fuβgönheim graph by Pierre-Alain Carrupt is gratefully acknowledged.) Printed in the Federal Republic of Germany Printed on acid-free paper ISBN 978-3-527-31755-4 Dedicated with love to my wife Barbara and my daughter Marion VII Contents List of Contributors XIX Preface XXIII A Personal Foreword XXV I Introduction 1 A Fresh Look at Molecular Structure and Properties 3 Bernard Testa, Giulio Vistoli, and Alessandro Pedretti 1.1 Introduction 3 1.2 Core Features: The Molecular “Genotype” 5 1.2.1 The Argument 5 1.2.2 Encoding the Molecular “Genotype” 6 1.3 Observable and Computable Properties: The Molecular “Phenotype” 6 1.3.1 Overview 6 1.3.2 Equilibria 8 1.3.3 Stereoelectronic Features 9 1.3.4 Recognition Forces and Molecular Interaction Fields (MIFs) 9 1.3.5 Macroscopic Properties 9 1.4 Molecular Properties and their Adaptability: The Property Space of Molecular Entities 10 1.4.1 Overview 10 1.4.2 The Versatile Behavior of Acetylcholine 11 1.4.3 The Carnosine–Carnosinase Complex 15 1.4.4 Property Space and Dynamic QSAR Analyses 19 1.5 Conclusions 21 2 Physicochemical Properties in Drug Profi ling 25 Han van de Waterbeemd 2.1 Introduction 26 2.2 Physicochemical Properties and Pharmacokinetics 28 2.2.1 DMPK 28 2.2.2 Lipophilicity – Permeability – Absorption 28 Molecular Drug Properties. Measurement and Prediction. R. Mannhold (Ed.) Copyright © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31755-4 VIII Contents 2.2.3 Estimation of Volume of Distribution from Physical Chemistry 30 2.2.4 PPB and Physicochemical Properties 30 2.3 Dissolution and Solubility 30 2.3.1 Calculated Solubility 32 2.4 Ionization (pKa) 32 2.4.1 Calculated pKa 33 2.5 Molecular Size and Shape 33 2.5.1 Calculated Size Descriptors 33 2.6 H-bonding 34 2.6.1 Calculated H-bonding descriptors 34 2.7 Lipophilicity 35 2.7.1 Calculated log P and log D 37 2.8 Permeability 37 2.8.1 Artifi cial Membranes and PAMPA 37 2.8.1.1 In Silico PAMPA 39 2.8.2 IAM, Immobilized Liposome Chromatography (ILC), Micellar Electrokinetic Chromatography (MEKC) and Biopartitioning Micellar Chromatography (BMC) 39 2.8.3 Liposome Partitioning 39 2.8.4 Biosensors 40 2.9 Amphiphilicity 40 2.10 Drug-like Properties 40 2.11 Computation versus Measurement of Physicochemical Properties 42 2.11.1 QSAR Modeling 42 2.11.2 In Combo: Using the Best of two Worlds 42 2.12 Outlook 43 II Electronic Properties and H-Bonding 3 Drug Ionization and Physicochemical Profi ling 55 Alex Avdeef 3.1 Introduction 55 3.1.1 Absorption, the Henderson–Hasselbalch Equation and the pH-partition Hypothesis 56 3.1.2 “Shift-in-the-pKa” 57 3.2 Accurate Determination of Ionization Constants 58 3.2.1 Defi nitions – Activity versus Concentration Thermodynamic Scales 58 3.2.2 Potentiometric Method 60 3.2.3 pH Scales 60 3.2.4 Cosolvent Methods 60 3.2.5 Recent Improvements in the Potentiometric Method Applied to Sparingly Soluble Drugs 61 3.2.6 Spectrophotometric Measurements 61 3.2.7 Use of Buffers in UV Spectrophotometry 62 3.2.8 pKa Prediction Methods and Software 63 Contents IX 3.2.9 Tabulations of Ionization Constants 63 3.3 “Octanol” and “Membrane” pKa in Partition Coeffi cients Measurement 63 3.3.1 Defi nitions 64 3.3.2 Shape of the Log Doct–pH Lipophilicity Profi les 65 3.3.3 The “diff 3–4” Approximation in log Doct–pH Profi les for Monoprotic Molecules 66 3.3.4 Liposome–Water Partitioning and the “diff 1–2” Approximation in log DMEM–pH Profi les for Monoprotic Molecules 67 3.4 “Gibbs” and Other “Apparent” pKa in Solubility Measurement 68 3.4.1 Interpretation of Measured Solubility of Ionizable Drug-Like Compounds can be Diffi cult 68 3.4.2 Simple Henderson–Hasselbalch Equations 68 3.4.3 Gibbs’ pKa and the “sdiff 3–4” Approximation 69 3.4.4 Aggregation Equations and “Shift-in-the-pKa” Analysis 72 3.5 “Flux” and other “Apparent” pKa in Permeability Measurement 74 FLUX 3.5.1 Correcting Permeability for the ABL Effect by the pK a Method 74 3.5.2 Membrane Rate-Limiting Transport (Hydrophilic Molecules) 76 3.5.3 Water Layer Rate-Limiting Transport (Lipophilic Molecules) 77 3.5.4 Ionic-species Transport in PAMPA 77 3.6 Conclusions 78 4 Electrotopological State Indices 85 Ovidiu Ivanciuc 4.1 Introduction 86 4.2 E-state Indices 87 4.2.1 Molecular Graph Representation of Chemical Structures 87 4.2.2 The Randiü–Kier–Hall Molecular Connectivity Indices 88 4.2.3 The E-state Index 89 4.2.4 Hydrogen Intrinsic State 90 4.2.5 Bond E-state Indices 90 4.2.6 E-state 3D Field 91 4.2.7 Atom-type E-state Indices 91 4.2.8 Other E-state Indices 91 4.3 Application of E-State Indices in Medicinal Chemistry 92 4.3.1 Prediction of Aqueous Solubility 93 4.3.2 QSAR Models 93 4.3.3 Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) 96 4.3.4 Mutagenicity and Carcinogenicity 100 4.3.5 Anticancer Compounds 102 4.3.6 Virtual Screening of Chemical Libraries 103 4.4 Conclusions and Outlook 105 X Contents 5 Polar Surface Area 111 Peter Ertl 5.1 Introduction 111 5.2 Application of PSA for Prediction of Drug Transport Properties 113 5.2.1 Intestinal Absorption 114 5.2.2 Blood–Brain Barrier Penetration 115 5.2.3 Other Drug Characteristics 117 5.3 Application of PSA in Virtual Screening 117 5.4 Calculation of PSA 119 5.5 Correlation of PSA with other Molecular Descriptors 121 5.6 Conclusions 123 6 H-bonding Parameterization in Quantitative Structure–Activity Relationships and Drug Design 127 Oleg Raevsky 6.1 Introduction 128 6.2 Two-dimensional H-bond Descriptors 129 6.2.1 Indirect H-bond Descriptors 129 6.2.2 Indicator Variables 131 6.2.3 Two-dimensional Thermodynamics Descriptors 131 6.3 Three-dimensional H-bond Descriptors 134 6.3.1 Surface H-bond Descriptors 134 6.3.2 SYBYL H-bond Parameters 136 6.3.3 Distance H-bond Potentials 136 6.4 Application of H-bond Descriptors in QSAR Studies and Drug Design 142 6.4.1 Solubility and Partitioning of Chemicals in Water–Solvent–Gas Systems
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