Molecular Drug Properties. Measurement and Prediction

504 Pages·2007·4.19 MB·English

by  Mannhold

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
Vol. 32
2006, ISBN 978-3-527-31087-6
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,
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[email protected] specifi cally marked as such, are not to be
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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 (∆logP = 0.6).
MLP
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 (pK) 32
a
2.4.1 Calculated pK 33
a
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-pK” 57
a
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 pK Prediction Methods and Software 63
a
Contents IX
3.2.9 Tabulations of Ionization Constants 63
3.3 “Octanol” and “Membrane” pK in Partition Coeffi cients
a
Measurement 63
3.3.1 Defi nitions 64
3.3.2 Shape of the Log D –pH Lipophilicity Profi les 65
oct
3.3.3 The “diff 3–4” Approximation in log D –pH Profi les for Monoprotic
oct
Molecules 66
3.3.4 Liposome–Water Partitioning and the “diff 1–2” Approximation in
log D –pH Profi les for Monoprotic Molecules 67
MEM
3.4 “Gibbs” and Other “Apparent” pK in Solubility Measurement 68
a
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’ pK and the “sdiff 3–4” Approximation 69
a
3.4.4 Aggregation Equations and “Shift-in-the-pK” Analysis 72
a
3.5 “Flux” and other “Apparent” pK in Permeability
a
Measurement 74
3.5.1 Correcting Permeability for the ABL Effect by the pK FLUX
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 Randi(cid:252)–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