Polypharmacology

List of Contributors xvii

Preface xxiii

1 Introduction 1
Juergen Bajorath

Part A Polypharmacology as a Safety Concern in Drug Discovery 9

2 The Safety Relevance and Interpretation of Compound Off-target Interactions 11
Eric A.G. Blomme, Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Terry R. Van Vleet, and Andy Vo

3 Off-target Activity and Adverse Drug Reactions 25
Dimitar Yonchev

4 Off-Target Screening Strategies 37
Sonia Roberts and Helen L. Lightfoot

5 Molecular Properties and Structural Motifs Related to Pharmacological Promiscuity 49
Jens-Uwe Peters

6 Kinase Liabilities in Early Drug Discovery 61
Stephan Kirchner

7 Activity at Cardiovascular Ion Channels 77
Ian M. Bell and Armando A. Lagrutta

Part B Polypharmacology as an Opportunity in Different Disease Areas 97

8 Toward Mechanism-based Therapies and Network Pharmacology 99
Cristian Nogales, Zina Piper, Zeinab Mamdouh, and Mayra Pacheco Pachado

9 Advancements in Rational Multi-Targeted Drug Discovery 109
Balaguru Ravikumar, Anna Cichonska, Navriti Sahni, Tero Aittokallio, and Rayees Rahman

10 Polypharmacology 127
Lynn L. Silver

11 Multi-Specific Binding Strategy 141
Yang Zhou, Shujing Xu, Dang Ding, Kai Tang, Xinyong Liu, Meehyein Kim, and Peng Zhan

12 Polypharmacology for the Treatment of Major Depressive Disorder 165
Tiffany Schwasinger-Schmidt

13 Multi-target Drugs to Treat Metabolic Diseases 175
Felix F. Lillich, Samaneh Goorani, Ewgenij Proschak, and John D. Imig

14 Overcoming the Challenges of Multi-Target-Directed Ligands for Alzheimer's Disease 193
Elisa Uliassi, Anna M. Pasieka, Eleonora Diamanti, and Maria Laura Bolognesi

15 The Role of Polypharmacology in the History of Drug Discovery 203
Axel Helmstaedter

Part C How to Discover Polypharmacological Drugs 213

16 Strategies for Multi-target Drug Discovery 215
Dayong Shi and Xiangqian Li

17 Predicting Polypharmacology with Web-Based Tools 223
Maedeh Darsaraee, Sacha Javor, and Jean-Louis Reymond

18 Using Phenotypic Screening to Uncover the Full Potential of Polypharmacology 237
Arsenio Nueda

19 Phenotypic Polypharmacology Drug Discovery for CNS Applications 251
Alberto Ambesi-Impiombato, Lee McDermott, Alan Lars Pehrson, and Daniela Brunner

20 Multi-target Peptides for the Treatment of Metabolic Diseases 269
Martin Bossart and Gerhard Hessler

21 The SOSA Approach to Drug Discovery 289
Norbert Handler, Michal Poznik, and Helmut Buschmann

Part D Polypharmacology, Classic Case Studies and Recent Research 319

22 Dual Inhibitors of CDK4/6 for Treating Cancer 321
Peter L. Toogood

23 Tapentadol, a Clinically Proven Analgesic with Two Mechanisms 339
Thomas Christoph, Helmut Buschmann, Norbert Handler, and Michal Poznik

24 Thalidomide - From a Banned Drug to Molecular Glues, PROTACs, and New Concepts in Drug Discovery 367
Junichi Yamamoto, Hiroshi Handa, and Yuki Yamaguchi

25 The Polypharmacology of Cariprazine and its Implications to Clinical Indications 385
Attila Egyed, Dora J. Kiss, and Gyoergy M. Keseru

26 Multi-Targeted Antivirals 405
Bing Ye, Letian Song, Meehyein Kim, Shenghua Gao, Peng Zhan, and Xinyong Liu

27 Multi-target Antimalarials as a Strategy to Reduce Resistance Risk 423
Lauren B. Coulson and Kelly Chibale

28 Multi-target Compounds for Tuberculosis 437
Giovanni Stelitano, Mario Cocorullo, and Laurent R. Chiarelli

29 Dual-acting HIV Inhibitors 451
Maria-Jose Camarasa, Ana-Rosa San-Felix, and Sonia de Castro

30 Multi-kinase Inhibitors for the Treatment of Pancreatic Cancer 463
Paul Dent and Andrew Poklepovic

Acknowledgements 467

References 467

Index 469

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• Química física
• Modelagem computacional e simulação
• Farmacologia
• Bioquímica

off-target adverse reactions; off-target activity; polypharmacological approaches; drug compound design; multi-target peptides; protein degraders; PROTACs; drug design; pharmacology; drug safety; Multi-Target Drug Discovery