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Girish Kumar Gupta, Vinod Kumar (Eds.)
Chemical Drug Design
De Gruyter Graduate
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Drug Metabolism and Personalized Therapy. Official journal of the European Society of Pharmacogenomics and Personalised Therapy
Adrián LLerena (Editor-in-Chief) ISSN 2363-8907, e-ISSN 2363-8915
Chemical Drug Design
Edited by Girish Kumar Gupta, Vinod Kumar
Editors
Dr. Girish Kumar Gupta Department of Pharmaceutical Chemistry M. M. College of Pharmacy Maharishi Markandeshwar University Mullana-133207, Ambala Haryana, India
Dr. Vinod Kumar Department of Chemistry Maharishi Markandeshwar University Mullana-133207, Ambala Haryana, India
ISBN 978-3-11-037449-0 e-ISBN (PDF) 978-3-11-036882-6 e-ISBN (EPUB) 978-3-11-039269-2
Library of Congress Cataloging-in-Publication data
A CIP catalog record for this book has been applied for at the Library of Congress.
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailedbibliographic data are available on the Internet at http://dnb.dnb.de.
© 2016 Walter de Gruyter GmbH, Berlin/Boston Typesetting: PTP-Berlin, Protago-TEX-Production GmbH, Berlin Printing and binding: CPI books GmbH, Leck Cover image: everythingpossible/iStock/thinkstock  Printed on acid-free paper Printed in Germany
www.degruyter.com
Preface
Today, drugs for practically every disease are available or in the process of developing to alleviate all diseases known to man and chemical drug design play an important role in finding new drugs or medicines based on the knowledge of a biological target. The drug molecules, generally organic substances, activate or deactivate the function of the biomolecules like proteins, lipids, carbohydrates, nucleic acids, etc. which in turn lead to the corresponding therapeutic benefits to the living being. Other classes of compounds including inorganic or organometallic compounds are also useful as drugs. Therefore, chemical drug design involves the design of small chemical com­pounds that can interact and bind efficiently to the biological target. In recent past, though an exhaustive study has been conducted in the field of drug design, there is still a great need of developing new drugs for future library. The present book is an attempt to present an invaluable and informative addition to field of drug design and discovery. The book contains eleven chapters contributed by international scientists and academicians focused on overview of basics in chemical drug design and the recent developments made in present scenario. The chapter 1 provides an overview of some basic techniques used in chemical drug design. The chapter 2 gives an update on recent developments in the field of drug designing paving the way for novel drug dis­covery and describes how knowledge of the state-of-art techniques has led research­ers to find out the best method for the development of new drugs. Chapter 3 enlight­ens the new concept of structure and ligand based drug designing. It also covers in detail about the 2D QSAR and 3D QSAR approaches, descriptors as well as different parameters used in QSAR studies. The chapter 4 describes the drug design applied to natural products against neglected diseases. It introduces general concepts, and discusses the neglected diseases, reporting on some of the enzymatic targets studied when developing new drugs to treat these ills. The chapter 5 describes the develop­ments made of newer hybrid drugs from natural products, especially for the treatment of infections and cancer. The advantage of this concept over a combinatorial chemis­try approach is the high diversity and the inherent biological activity of the hybrids. The chapter 6 describes how does the drug metabolism play a major role in the drug design and discovery process and determine the fate of the prospective drugs. In chapter 7, the anticancer rationale of mistletoe lectins (the carbohydrate-binding pro­teins) is discussed. Its mechanism of discrimination between cell surface antigens of normal and cancer cells is also emphasized. The chapter 8 highlights the structural­activity relationship of different classes of typical and atypical antipsychotic drugs and provides some considerations concerning new treatment research. The chapter 9 describes the applications of high performance chromatographic techniques in the standardization of herbal drugs. The study focuses on the various chromatographic techniques, chemometric tools and interpretation of results by HCA & PCA in various guggulu samples. In chapter 10, the role of copper and its complexes with reference to toxicity level, sources, progress in the development of drugs and various important
VI Preface
discussions about the mode of action is discussed. Finally, chapter11 highlights the various thiazole-containing drugs which are currently on the market or in clinical trials are discussed with a special note on their synthesis and mechanism of biologi­cal action.
The target audience of the book include students, researchers, chemists, phar­macists and professionals who are involved in different studies related to medicinal chemistry and drug design. We would like to acknowledge all the authors for their contribution and assembled the whole book. We hope that it will enhance the knowl­edge of scientists towards various approaches for drug design and would encourage them to dedicate their future research in understanding of relevant mechanisms and applications for the development of novel therapeutics. With this we signed off by reminding you to send feedbacks with your critiques and communiqués.
Girish Kumar Gupta Vinod Kumar
Table of Contents
PrefaceV
Sreekanth Thota
1 Overview of chemical drug design
1.1 Drug design
1.2 Rational drug design
1.3 Ligand-based drug design
1
2
5
1.4 Structure-based drug design
1.5 Pharmacophore-based approaches
1.6 Structure-based approaches
1.7 New lead generation
1.8 Structure evaluation
1.9 Future directions
8
9
9
Meenakshi Rajpoot, Rajasri Bhattacharyya, Girish Kumar Gupta, Anil K. Sharma
2 Drug designing in novel drug discovery: Trends,scope and relevance
2.1 Introduction
2.2 Drug designing
2.3 Applications of SBDD
2.4 Applications of LBDD
15
16
24
25
2.5 Role of cheminformatics in drug discovery
2.6 Conclusion
26
1
6
8
8
26
15
Sumitra Nain, Garima Mathur, Girish Kumar Gupta, Sarvesh Paliwal
3 Structure- and ligand-based approaches in drug designing
3.1 Drug discovery
3.2 Drug design
3.3 Drug designing techniques
3.4 Quantitative Structure-Activity Relationship (QSAR)
3.5 Physicochemical parameters
3.6 Biological parameters
3.7 Statistical terms in QSAR
31
33
33
35
35
44
48
31
Luciana Scotti, Francisco J. B. Mendonça Júnior, Marcelo S. daSilva, Marcus T. Scotti
4 Drug design applied to natural products against neglected diseases
4.1 Natural products
4.2 Medicinal chemistry
4.3 Docking
58
4.4 Neglected diseases
4.5 Final considerations
53
56
59
79
53
VIII Table of Contents
Manu Sharma
5 Natural product hybrid compounds as drug leads
5.1 Introduction
87
5.2 Naturally occurring hybrids/conjugates of natural products
5.3 Synthetic hybrids of whole natural products
5.4 Conclusion
102
87
88
91
Komarla Kumarachari Rajasekhar
6 Drug metabolism
6.1 Introduction
6.2 Phase I Metabolic reactions
6.3 Oxidative mechanisms
6.4 Reductive reactions
6.5 Hydrolytic reactions
6.6 Phase II conjugation reactions
6.7 Factors affecting drug metabolism
107
107
108
114
139
145
148
156
Seema Patel and Girish Kumar Gupta
7 Mistletoe lectin: A promising cancer therapeutic
7.1 Introduction
165
7.2 Anticancer potency of bacteria/plant lectins
165
167
7.3 Anticancer potency of mistletoe and the underlying mechanisms
7.4 Mistletoe lectins
7.5 Future directions
7.6 Concluding remarks
170
174
175
168
Tamara Angelo and André São Pedro
8 Antipsychotics
8.1 Introduction
8.2 History
183
8.3 Etiology of schizophrenia and related psychoses
8.4 Potential mechanism of action of antipsychotics
183
183
184
185
8.5 Structure-activity relationships and pharmacology of the drugs
8.6 Research into future treatments for schizophrenia and related
psychoses
194
Prerna Sarup
9 Chemometric analysis: A novel tool for herbal drug analysis and
designing
9.1 Introduction
9.2 Experimental
9.3 Data analysis and quality evaluation
199
199
201
202
186
Table of Contents IX
9.4 Results and discussion
9.5 Conclusion
212
204
Subash Chandra Sahoo, Ramesh Kataria and S.K. Mehta
10 Copper and its complexes: A pharmaceutical perspectives
10.1 Introduction
10.2 Source of dietetic copper
215
217
10.3 Recommended concentration of copper for human diet
10.4 Copper consumption and suggestions
10.5 Mechanism of copper transport in humans
10.6 Copper deficiency and symptoms
10.7 Copper metabolism and major diseases
218
218
219
220
10.8 Copper metabolism and hypothesized health problems
215
217
223
10.9 Copper complexes as an emerging tool in pharmaceutical sciences
10.10 Concluding remarks
236
Sunil Kumar, Madhuri T. Patil, Ramesh Kataria, DeepakB.Salunke
11 Thiazole: A privileged scaffold in drug discovery
11.1 Introduction
243
11.2 Synthetic routes for the construction of the thiazole ring
11.3 Thiazole as privileged scaffold in synthetic drugs
11.4 Ritonavir
11.5 Nitazoxanide
11.6 Sulfathiazole
11.7 Thiabendazole
11.8 Fatostatin
11.9 Dasatinib
11.10 Tiazofurin
11.11 CYC116
11.12 NCH-31
11.13 TAK-715
11.14 Meloxicam
11.15 Nizatidine
11.16 Famotidine
11.17 Conclusion
252
259 260
262
263
265
267 268 269
271
272
274
275 277
243
247
252
231
Index
283