Progress in Drug Research VoI. 58 Edited by Ernst Jucker, Basel Board of Advisors Joseph M. Colacino Pushkar N. Kaul Vera M. Kolb J. Mark Treherne Q. MayWang Authors Jay A. Glasel Vera M. Kolb Paul L. Skatrud John W. Ford, Edward B. Stevens, J. Mark Treherne, Jeremy Packer and Mark Bushfield David T. Wong and Frank P. Bymaster Satya P. Gupta Springer Basel AG Editor Dr. E. Jueker Steinweg 28 CH-4107 Ettingen Switzerland e-mail: [email protected] Visit our PDR homepage: http://www.birkhauser-science.com ISBN 978-3-0348-9468-5 ISBN 978-3-0348-8183-8 (eBook) DOI 10.1007/978-3-0348-8183-8 The Publisher and Editor cannot assume any legal responsibility for information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use. This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broad casting, reproduction on microfilrns or in other ways, and storage in data banks. For any kind of use permission of the copyright owner must be obtained. © Springer Sasel AG 2002 Originally published by Sirkhăuser Verlag 2002 Member of the BertelsmannSpringer Publishing Group Printed on acid-free pa per produced from chlorine-free pulp. TCF 00 Cover design and layout: Groflin Graphic Design, Basel ISBN 3-7643-6624-9 987654321 Contents Drugs, the human genome, and individual-based medicine ........... . By Jay A. Glasel Herbal medicine of Wisconsin Indians 51 By Vera M. Kolb The impact of multiple drug resistance (MDR) proteins on chemotherapy and drug discovery ......................................... 99 By Paul L. Skatrud Potassium channels: Gene family, therapeutic relevance, high-throughput screening technologies and drug discovery.......... 133 By John W. Ford, Edward B. Stevens, J. Mark Treherne, Jeremy Packer and Mark Bushfield Dual serotonin and noradrenaline uptake inhibitor class of antidepressants - Potential for greater efficacy or just hype? ........... 169 By David T. Wong and Frank P. Bymaster Advances in QSAR studies of HIV-1 reverse transcriptase inhibitors.... 223 By Satya P. Gupta Index Vol. 58 ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265 Index of titles, Vol. 1-58...................................................... 273 Author and paper index, Vol. 1-58.......................................... 289 Foreword by the Editor This 58th volume of the series Progress in Drug Research contains six reviews which all highlight latest insights and discoveries in drug research and appli cation. The first article is devoted to problems associated with individual based medicine. One of the consequences of the "genomic revolution" is the recognition that individuals differ from one another in sequence variations in their genomes. This led to the optimistic assumption that an individual's pattern of sequence variations could lead to drugs that target that individual's variant proteins and make individual-based medicine possible. Jay Glasel examines these possibilities, and comes to the conclusion that the human genome is only one of the elements serving to maintain an organism's inter action with its environment. The next article is very much in line with efforts to make use of natural sources as valuable addition to the modern agents in the instrumentarium of today's therapeutic methods. This masterly review by Vera Kolb is a valuable addendum to a number of reviews published in PDR, e.g. on Chinese Medicine, on herbal drugs and on drugs of maritime origin. Vera Kolb is in full agreement with the Editor, believing that alternative med icine offers more possibilities than is recognised today. The next review deals with multiple drug resistance proteins. Bacterial and viral infections, as well as infections with fungi and/or parasites, increasingly pose problems or even unsurmountable barriers towards successful chemotherapy. On the other hand, multiple drug resistance proteins also pre sent several positive opportunities, and Paul Skatrud highlights in this excel lent review both sides of the problem. Existing drugs that modulate ion chan nels represent a key class of pharmaceutical agents across many therapeutic areas and there is considerable further potential for potassium channel drug discovery. In this respect, it is of utmost importance to identify lead com pounds that can provide tractable starting points for medicinal chemistry. Several potassium channel screening platforms are described in the fourth review by John W. Ford et aI., and particular emphasis is placed on the mech anistic basis of drug-target interaction in potassium channel discovery. Improvement of existing and creation of new antidepressant drugs is still of great importance for the treatment of major depressive disorder. It has been recognized that promotion of serotonergic and noradrenergic transmission by inhibiting simultaneously the uptake of serotonin and noradrenaline could potentially result in improved antidepressant agents. vii In this fifth review, David Wong and Frank P. Bymaster demonstrate the lat est achievements in this field of research and provide new impulse for studies which can lead to new, potent antidepressants. Finally, in the last review, Satya Gupta continues with his extensive studies of QSAR analysis and surveys lat est results with HIV-1 reverse transcriptase inhibitors, making an important addition to reviews on this subject previously published in PDR. The topical ity and importance of such studies need not be stressed anymore. All these six reviews contain extensive bibliographies, thus enabling the interested reader and the active researcher to have easy access to the original literature. The various indices facilitate the use of these monographs and also help to use PDR as an encyclopedic source of information in the complex and fast growing field of drug research. The series Progress in Drug Research was founded in 1958/59. In the 43 years of its existence, drug research has undergone drastic changes, but the original purpose of these monographs remains unchanged: dissemination of informa tion on trends and developments, discussion of crucial points and creation of new prospects on future drug design. The Editor is anxious to maintain the high standard of PDR and is grateful to the authors for their willingness to undertake the hard work of writing comprehensive review articles for the ben efit of all involved with drug research. It is their high qualification and expe rience on which the success of these monographs is based. In ending this Foreword, I would like to thank the authors for their contri bUtions, the Members of the Board of Advisors foir their active help and advice and the reviewers for improving these monographs. Last but not least, I am greatly indebted to Birkhauser Publishers and in particular to Beatrice Menz and Gabriele FertOsz6gi, Editorial Department BioSciences, for their active par ticipation with editing and producing this new volume. Hans-Peter Ebneter, Bernd Luchner, Eduard Mazenauer and Gregor Messmer have contributed their vast experience and intimate knowledge. My sincere thanks are due also for their personal engagement and for the rewarding, harmonious cooperation. My very special thanks go to Mr. Hans-Peter Thiir, Birkhauser Publishing's CEO. For the many decades of our close cooperation Mr. Thiir gave PDR and its Editor his full support and never ceased to give this series impulses which go far beyond his function as CEO. I would like to acknowledge that some of the most valuable review articles have been a result of Mr. Thiir's suggestion, and it is also due to his encouragement that I continue with great enthusiam with the editorship of this series of monographs. Basel, April 2002 Dr. E. Jucker Progress in Drug Research, Vol. 58 (E. lucker, Ed.) ©2002 Birkhauser Verlag, Basel (Switzerland) Drugs, the human genome, and individual based medicine By Jay A. Glasel Global Scientific Consulting LLC 15 Colton St. Farmington, CT 06032, USA <[email protected]> Jay A. Glasel studied Chemistry and Physics at the California Insti tute of Technology and received his PhD. in Chemical Physics at the University of Chicago. He is managing member of Global Scientific Consulting LLC in Farm ington, Connecticut and Professor Emeritus ofB io chemistry at the University of Connecticut Medical Dental School. He is senior author of an extensive list of research articles in scientific publications. Summary The so-called "Genomic Revolution" has made possible the high-resolution sequencing of the DNA making up the human genome. One of the main con clusions of the currently available sequencing data is that individuals differ genetically from one another via sequence variations in their genomes. When affected genes are transcribed and translated, some of these sequence varia tions result in protein products that may affect the functioning of the pro teins. This has led to widespread optimism that information on an individ ual's pattern of sequence variations will lead to drugs that target that indi vidual's variant proteins and make "individual-based medicine" possible. In this chapter some of the assumptions underlying the proposed production of individual drug treatments are examined. The assumptions are viewed in the light of very recent experimental evidence about the sequence patterns found in humans. Also discussed are ancillary ethical problems in cataloging and using databases containing individuals' sequence data, what human genomic sequences are revealing about the use of animal models in devel oping drugs, and how evidence is mounting that the human genome is only one element serving to maintain an organism's interaction with its environ ment. Drugs, the human genome, and individual-based medicine Contents 1 Introduction .................................................................... . 6 1.1 Drugs, the genome, proposals for "individual medicine" .................... . 6 1.1.1 The genetic basis for the concept of individual medicine .................... . 7 1.1.2 Present progress in obtaining genomic SNP information .................... . 8 1.1.3 Will genomics have an impact on clinical and pharmaceutical medicine? .. 8 1.2 The need for new ideas in drug development .............. .. .............. .. 9 2 Viewpoints on health and disease ............................................. . 12 2.1 Theoretical basis for "individual medicine" ............... . 12 2.1.1 The genetocentric viewpoint of health and disease 13 2.1.2 The epigenetic viewpoint of health and disease 14 2.2 Cytoplasmic inheritance and epigenetics 14 2.2.1 Cytoplasmic inheritance .. 14 2.2.2 Epigenetics ................................................. . 17 2.2.3 Single-and multi-genic disease ................................................ . 18 3 Drugs and human genomics ............................ . 20 3.1 An abbreviated history of pharmacogenomics ........................ . 20 3.1.1 Drugs and ethnicity .................................................... . 21 3.1.2 Ethical considerations ......................................................... . 21 3.2 Metabolic pharmacogenomics ............................................... .. 22 3.3 What is the extent of human genomic heterozygosity? ...................... . 23 3.3.1 Results from the human genome projects ......... . 23 3.3.2 SNP evidence from direct sequencing .............. . 25 3.3.3 Conservative and radical changes in polypeptides ........................... . 28 3.3.4 Summary of preliminary SNP work .. 30 4 The molecular genetics of asthma ................................. . 31 4.1 Asthma, the disease ................................................ . 31 4.2 Drug treatment for asthma .............................................. . 32 4.3 The genome and asthma ....................................................... . 33 4.3.1 SNPs in the ~2-AR gene ........................................................ . 33 4.3.2 SNPs in the ~2-AR gene; clinical correlates .................................... . 34 4.3.3 Conclusions from this study ................................................... . 36 5 Genomic and non-genomic effects mediated by the glucocorticoid receptor . 38 5.1 Genomic effects ................................................................ . 38 5.2 Non-genomic effects ............ . 39 6 Animal models in the genomic era of drug research 42 7 Conclusions and future directions ............................................ . 44 7.1 Metabolic pharmacogenomics ...................................... . 44 7.2 Personalized drugs ............................................................. . 45 7.3 Animal models ...................................................... .. 46 7.4 Ethical considerations ......................................................... . 47 References ...................................................................... . 48 3 Jay A. Glasel Keywords Pharmacogenetics, pharmacogenomics, epigenetics, human genome, single nucleotide poly morphisms, molecular genetics, individual medicine, drug development. Glossary of abbreviations Anchored re-sequencing strategy: An expensive approach to obtaining a large number of SNPs using short sequences of DNA from individuals of different ethnic groups that are derived from a plasmid library. These sequences are then compared to the genome draft sequence to obtain a large number of SNPs in a very short amount of time. Annotation (annotated sequence): A term used with very little consistency among researchers working on genome-related projects. As commonly used, annotation entails assembling infor mation of several distinctive types, starting with refined DNA sequence data but extending beyond that level to varying degrees of complexity. For example, completed DNA sequence infor mation may be segmented into distinct intervals that may be demarcated in terms of their encod ing specific types of product, such as proteins. Next, a particular gene may be annotated in such terms as its protein coding region, its transcript, promoter region, and so forth. At a higher level of annotation, a protein that is encoded by a particular gene may be annotated in terms of its physical attributes, such as molecular weight, membrane spanning regions, structural domains, or three-dimensional structure. Annotation at the level of comparative biology may include infor mation linking a particular protein from a specific organism to similar proteins from other organ isms or to members of similar protein families. Genes may also be annotated at a functional level, in terms of their respective roles in cellular metabolism, a particular systematic enzyme number (EC) deSignation, protein-protein interactions, and expression profiles. Contigs (contig map): Overlapping (contiguous) DNA segments assembled from sequenced fragments of a chromosome. A contig map is the sequence of DNA in a chromosome constructed by isolating contigs. Epigenetics: The study of heritable changes in gene expression that occur without a change in DNA sequence. EST: Expressed sequence tag, several hundred base pairs of known cDNA sequence flanked by PCR primers. Because they are derived from cDNA libraries (Le., from reverse transcription of cellular mRNAs), ESTs represent portions of expressed genes. ESTs are useful for identifying full length genes and a landmark for mapping. Finished sequence: Complete sequence of a clone or of a genome with an accuracy of at least 99.99% and no gaps. Functional genomics: The study of genomes to determine the biological function of all the genes and their products. Genetic map: The ordering of genes on chromosomes according to their recombination fre quency during meiosis. The unit of distance is centimorgans (cM) which corresponds to a 1% 4