Smith and Williams' Introduction to the Principles of Drug Design and Action

568 Pages·2019·24.198 MB·English

by  Smith, H. John, Williams, Hywel

Smith and Williams'
Introduction to the Principles of
Drug Design and Action
Third edition

Smith and Williams'
Introduction to the Principles of
Drug Design and Action
Third edition
Edited by
H. John Smith
Welsh School of Pharmacy
University of Wales
Cardiff, UK
he harwood academic publishers
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Copyright© 1998 OPA (Overseas Publishers Association) Amsterdam B.V.
Published under license under the Harwood Academic Publishers imprint, part of
The Gordon and Breach Publishing Group.
All rights reserved.
First Edition published 1983
Second Edition published 1988
No part of this book may be reproduced or utilized in any form or by any means,
electronic or mechanical, including photocopying and recording, or by any information
storage or retrieval system, without permission in writing from the publisher. Printed in
Singapore.
Amsteldijk 166
1st Floor
1079 LH Amsterdam
The Netherlands
British Library Cataloguing in Publication Data
Smith and Williams' introduction to the principles of drug design and action. - 3rd ed.
1. Drugs - Design 2. Pharmacology
I. Smith, H. J. (Harold John), 1930 - II. Williams, Hywel
III. Introduction to the principles of drug design and action
615.1
ISBN 90-5702-037-8 (hard cover)
Front cover: A model of the active site of aromatase with the substrate audiosteredione
(yellow) as described by C.H. Laughton eta!. (1993) Journal ofS teroid Biochemistry and
Molecular Biology 44,399-407.
CONTENTS
Preface vii
List of Contributors ix
Abbreviations XI
Chapter 1 Processes of Drug Handling by the Body
D K Luscombe and P 1 Nicholls
Chapter 2 The Design of Drug Delivery Systems
I W Kellaway 28
Chapter 3 Intermolecular Forces and Molecular Modelling
R H Davies and D Timms 51
Chapter 4 Drug Chirality and its Pharmacological Consequences
A 1 Hutt 97
Chapter 5 Quantitative Structure-Activity Relationships and Drug Design
1 C Dearden and F K C James 167
Chapter 6 From Programme Sanction to Clinical Trials: A Partial View of the
Quest for Arimidex™, a Potent, Selective Inhibitor of Aromatase
P N Edwards 208
Chapter 7 Pro-Drugs
A W Lloyd and H 1 Smith 236
Chapter 8 Design of Enzyme Inhibitors as Drugs
A Patel, H 1 Smith and 1 Stiirzebecher 261
Chapter 9 The Chemotherapy of Cancer
DE Thurston and S G M 1 Lobo 331
Chapter 10 Neurotransmitters, Agonists and Antagonists
R D E Sewell, R A Glennon, M Dukat, H Stark, W Schunack
and P G Strange 387
vi CONTENTS
Chapter 11 Design of Antimicrobial Chemotherapeutic Agents
E G M Power and AD Russell 434
Chapter 12 Recombinant DNA Technology: Monoclonal Antibodies
F J Rowell and J R Furr 491
Chapter 13 Bio-inorganic Chemistry and its Pharmaceutical Applications
D M Taylor and DR Williams 509
Index 539
PREFACE
The second edition of Introduction to the Principles of Drug Design was published in
1988. In the intervening years considerable strides have been made in the approaches to
rational drug design as the result of the flood of knowledge coming from advances made
in molecular biology. This has provided a better understanding of biological systems in
terms of their structural components, cellular signalling, genomic modulation etc.,
leading to a more informed approach to chemotherapeutic intervention in disease.
In the third edition the aims and objectives, as well as the intended reading audience,
remain the same as in previous editions but all the chapters have been revised to take into
account of new developments in their subject areas and three new chapters have been
included. Chapter 4 dealing with Drug Chirality and its Pharmacological Consequences
reviews an ongoing field of considerable importance to pharmacologists and especially
industrial concerns in view of the recent requirements imposed by Regulatory Bodies
regarding drug registration. Chapter 6 provides a fascinating account of the difficulties
inherent in the development of a drug from the bench to the clinic and brings out the
trials and tribulations encountered by the multi-disciplinary research teams involved.
Chapter I 0 on Neurotransmitters, Agonists and Antagonists compensates to some extent
for an area neglected in previous editions, that is, the design of drugs for action on the
central nervous system, and also provides an account of membrane-bound receptors
perhaps overshadowed in previous editions by emphasis on enzyme and DNA related
targets.
Chapter 3 on Intermolecular Forces and Molecular Modelling has required expansion
and revision due to advances in the techniques relating to ligand-receptor interactions and
we are indebted to Zeneca, through Dr M.T. Cox, for their generosity in meeting the
considerable cost of reproducing the necessary new colour plates in the book. We also
wish to thank Dr Charlie Laughton of the School of Pharmacy, Nottingham University
for providing the illustration on the front cover of the book.

LIST OF CONTRIBUTORS
Chapter 1
Professor David K Luscombe and Professor Paul J Nicholls
Welsh School of Pharmacy, University of Wales Cardiff, CardiffCFl 3XF, UK
Chapter 2
Professor Ian W Kellaway
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFI 3XF, UK
Chapter3
Dr Robin H Davies
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFI 3XF, UK
Dr David Timms
Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SKIO 4TG, UK
Chapter4
Dr Andrew J Hutt
School of Pharmacy, Kings College, University of London, Manresa Road, London
SW3 6LX, UK
ChapterS
Professor John C Dearden
School of Pharmacy, John Moores University, Byrom Street, Liverpool, L3 3AF, UK
tDr Kenneth C James
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFl 3XF, UK
Chapter6
Dr Philip N Edwards
Zeneca Pharmaceuticals, CAM Department, Alderley Park, Macclesfield, Cheshire
SK104TG, UK
Chapter7
Dr Andrew W Lloyd
Department of Pharmacy, University of Brighton, Cockcroft Building, Moulescoombe,
Brighton BN2 4GJ, UK
Dr H John Smith
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFl 3XF, UK
X LIST OF CONTRIBUTORS
Chapter 8
Dr Anjana Patel
The Royal Pharmaceutical Society, Lambeth High Street, London SEI 7JN, UK
Dr H John Smith
Welsh School of Pharmacy, University of Wales Cardiff, CardiffCFl 3XF, UK
Dr Ji:irg Sti.irzebecher
Klinikum der Universitat Jena, Zentrum ftir vasculiire Biologie und Medizin,
Institut fiir Biochemie und Moleckularbiologie, Nordhauser Strasse 78,
D-99089 Erfurt, Germany
Chapter9
Professor David E Thurston and Dr Sylvia G M Lobo
School of Pharmacy and Biomedical Sciences, University of Portsmouth,
Park Building, King Henry I Street, Portsmouth POl 2DZ, UK
Chapter 10
Dr Robert D E Sewell
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFI 3XF, UK
Professor Richard A Glennon and Dr Malgorzata Dukat
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298--0540 USA
Dr Holger Stark and Professor Walter Schunack
Freie Universitat Berlin, Institut fiir Pharmazie\ Ki:inigin-Luise-Strasse 2 + 4,
D-14195 Berlin, Germany
Philip G Strange
Research School of Biosciences, The University, Canterbury CT2 7NJ, UK
Chapter 11
Dr Edward G M Power
Department of Microbiology, United Medical and Dental Schools, Guy's Hospital,
London Bridge, London SEI 9RT, UK
Professor A Denver Russell
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFI 3XF, UK
Chapter 12
Professor Frederick J Rowell
School of Health Sciences, University of Sunderland, Pasteur Building,
Sunderland SRI 3SD, UK
Dr James R Furr
Welsh School of Pharmacy, University of Wales Cardiff, Cardiff CFI 3XF, UK
Chapter 13
Professor David M Taylor and Professor David R Williams
Chemistry Department, University of Wales Cardiff, CardiffCFl 3XF, UK