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Polypharmacology
Strategies for Multi-Target Drug Discovery
Jens-Uwe Peters (Edited by), JU Peters (Author)
9781394182831, Wiley
Hardback, published 23 January 2025
512 pages
1 x 1 x 1 cm, 0.454 kg
Practical guide to navigate problems involved with promiscuous ligands and multi-target drug discovery, supported by case studies and real examples Polypharmacology covers the two-sided nature of polypharmacology: its relevance for adverse drug effects, as well as its benefit for certain therapeutic drug classes in effectively treating complex diseases like psychosis and cancer. The book provides practical guidelines and advice to help readers design drugs that have multiple targets while minimizing unwanted off-target effects, discusses important disease areas like viral infection, diabetes, and obesity that have advanced significantly in the last decade, and guides researchers in neighboring areas to polypharmacology. The book is divided into four parts. Part A covers the link between off-targets and adverse drug reactions, how to screen for off-target activity, and how to recognize and optimize compounds with a potential for off-target activity. Part B discusses disease areas which benefit from polypharmacological approaches. Part C highlights important approaches, such as compound design, data mining with web-based tools, and multi-target peptides. Part D provides case study coverage on topics like CDK4/6 inhibitors for cancer treatment, the potential of multi-target ligands for COVID, and protein degraders and PROTACs. Sample topics discussed in Polypharmacology include: Delivering the latest research developments in the field, Polypharmacology is an essential reference on the subject for medicinal chemists, pharmacologists, biochemists, computational chemists, and biologists, as well as pharmaceutical professionals involved in drug discovery programs.
List of Contributors xvii Preface xxiii 1 Introduction 1 1.1 Origins 1 1.2 Pros and Cons 1 1.3 Discovery and Design 2 1.4 Structural Data 2 1.5 Activity Data 3 1.6 Drug Target Estimates 4 1.7 Explainable Machine Learning 5 1.8 Conclusion 6 References 6 Part A Polypharmacology as a Safety Concern in Drug Discovery 9 2 The Safety Relevance and Interpretation of Compound Off-target Interactions 11 2.1 Introduction 11 2.2 Assessing Off-Target Interactions of Small Molecules 12 2.3 Interpretation of Data from Secondary Pharmacology Assays 13 2.4 Off-Target Interactions of Biologics: Polyreactivity and Polyspecificity 14 2.5 Case Study Examples 16 2.6 Physicochemical Properties 18 2.7 In Silico Methods to Predict Off-Target Interactions 19 2.8 Predicting Antibody Specificity 19 References 21 3 Off-target Activity and Adverse Drug Reactions 25 3.1 Personal Perspective 25 3.2 Introduction 25 3.3 Secondary Pharmacology and Adverse Drug Reactions 26 3.4 A Practical Perspective 31 Acknowledgments 33 References 34 4 Off-Target Screening Strategies 37 4.1 Introduction 37 4.2 Small Molecules 37 4.3 Proteolysis-Targeting Chimeras (PROTACs) 39 4.4 Small Molecules Targeting RNA (smRNA) 41 4.5 Antisense Oligonucleotides 43 4.6 Large Molecules 43 4.7 Regulatory Aspects 44 4.8 Future Outlook 45 Acknowledgments 45 Addendum 45 References 45 5 Molecular Properties and Structural Motifs Related to Pharmacological Promiscuity 49 5.1 Introduction 49 5.2 Basicity and Protonation State 49 5.3 Lipophilicity 52 5.4 Molecular Weight 54 5.5 Other Parameters 54 5.6 Structural Motifs 54 5.7 Conclusion 56 References 57 6 Kinase Liabilities in Early Drug Discovery 61 6.1 Introduction 61 6.2 Protein Kinases and Inhibitor Binding Sites 61 6.3 Kinase-regulated Cardiac Functions and Potential Consequences of Inhibition 64 6.4 Core Kinases Driving the Cell Division Cycle and Consequences of Interference 64 6.5 Cell Cycle Checkpoints Controlling Cell Division 69 6.6 Selectivity Profiling of Kinase Inhibition 71 References 72 7 Activity at Cardiovascular Ion Channels 77 7.1 Introduction 77 7.2 Screening Methods 79 7.3 Structural Insights into the Interaction Between Drugs and CV Ion Channels 80 7.4 Medicinal Chemistry Approaches 85 7.5 Conclusion 90 References 91 Part B Polypharmacology as an Opportunity in Different Disease Areas 97 8 Toward Mechanism-based Therapies and Network Pharmacology 99 8.1 A Crisis in the Pharmaceutical Industry 99 8.2 Disease Modules as Targets for Precision Medicine 99 8.3 Mechanism-based Therapies and Network Pharmacology 101 8.4 Implementing Mechanism-based Therapies 103 8.5 Summary and Conclusions 105 References 106 9 Advancements in Rational Multi-Targeted Drug Discovery 109 9.1 Introduction 109 9.2 Cancer and the Existing Treatment Strategies 109 9.3 Safety and Efficacy: A Double-Edged Sword 114 9.4 Rational Design of MTDs 116 9.5 Perspective, Limitations, and Challenges 120 References 120 10 Polypharmacology 127 10.1 Introduction 127 10.2 The Failure of Single-target-based Discovery of Antibiotics 127 10.3 Attempts at Purposeful Multitargeting 128 10.4 Cell Surface Targets and Macrocyclic Peptides (MCPs) 131 10.5 Conclusions 136 References 136 11 Multi-Specific Binding Strategy 141 11.1 Proteolysis Targeting Chimera (PROTAC) 142 11.2 Antibody Recruiting Molecules 147 11.3 Antibody-Drug Conjugates (ADCs) 150 11.4 Antiviral Drug Delivery Systems 151 11.5 Ribonuclease Targeting Chimeras 155 11.6 Other Bifunctional Small Molecules 157 11.7 Summary and Outlook 159 References 160 12 Polypharmacology for the Treatment of Major Depressive Disorder 165 12.1 Introduction 165 12.2 Multitargeted Antidepressants 166 12.3 Conclusions 170 References 171 13 Multi-target Drugs to Treat Metabolic Diseases 175 13.1 Introduction 175 13.2 Metabolic Diseases and Current Treatment Approaches 175 13.3 Strategies to Develop Multi-target Drugs for Metabolic Diseases 177 13.4 Approaches Involving Modulation of PPARs and Other Metabolically Relevant Nuclear Receptors 180 13.5 Approaches Involving Inhibition of DPP4 181 13.6 Diverse Target Combinations for Polypharmacological Treatment of Metabolic Disorders 183 13.7 Conclusion 184 References 185 14 Overcoming the Challenges of Multi-Target-Directed Ligands for Alzheimer’s Disease 193 14.1 Introduction 193 14.2 Target Identification: In the Search for New Target Pairs 193 14.3 PK Challenges in MTDL Optimization 195 14.4 Phenotypic Screening: In a Search for an Early Proof-of-Concept 197 14.5 Conclusions 199 References 199 15 The Role of Polypharmacology in the History of Drug Discovery 203 15.1 Introduction: Drug Discovery in the Twentieth Century 203 15.2 Natural Products 205 15.3 Historical Drugs with Multiple Actions 206 15.4 From Serendipity to Concept: Repurposing and Polypharmacology 209 References 210 Part C How to Discover Polypharmacological Drugs 213 16 Strategies for Multi-target Drug Discovery 215 16.1 Introduction 215 16.2 Rational Design of Multitargeted Ligands 215 16.3 Discussion and Conclusion 220 References 220 17 Predicting Polypharmacology with Web-Based Tools 223 17.1 Introduction 223 17.2 Pass 223 17.3 Sea 226 17.4 Super-PRED 226 17.5 TargetHunter 227 17.6 SwissTargetPrediction 227 17.7 TargetNet 229 17.8 PPB 229 17.9 PPB2 230 17.10 Comparison of Different Web-Based Tools 231 17.11 Conclusion 233 Acknowledgement 233 References 233 18 Using Phenotypic Screening to Uncover the Full Potential of Polypharmacology 237 18.1 Introduction: Phenotypic Screening and Phenotypic Drug Discovery 237 18.2 Polypharmacology Discovered Using Phenotypic Screening 239 18.3 PDD Strategies to Discover Novel Polypharmacology 240 18.4 Optimizing Polypharmacology in Phenotypic Screening Hits 242 18.5 Understanding the MoA from a PDD and Polypharmacology Perspectives 245 18.6 The Path to Virtual PDD-Derived Polypharmacology 246 18.7 Conclusions and Future Directions 246 References 248 19 Phenotypic Polypharmacology Drug Discovery for CNS Applications 251 19.1 Introduction 251 19.2 BPDD Lessons from the History of Psychopharmacology 251 19.3 Current Trends in Psychopharmacology 253 19.4 A Machine Learning-Based System for Global Behavior Profiling for CNS Drug Discovery 255 19.5 Modeling Chemical and Phenotypic Relationships of Compounds Screened in SmartCube® 257 19.6 Privileged Scaffolds and BPDD with SmartCube® 260 19.7 Ulotaront (SEP-363856) a BPDD Case Study 261 19.8 Conclusions 262 References 263 Appendix 266 20 Multi-target Peptides for the Treatment of Metabolic Diseases 269 20.1 Introduction 269 20.2 Glucagon-like Peptide-1 (GLP-1) Receptor Agonists 269 20.3 Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the One-pharmacophore Approach 270 20.4 GLP-1 Receptor/Glucagon Receptor Dual Agonists 272 20.5 Clinical Advanced GLP-1/GCGR Dual Agonists 275 20.6 GLP-1 Receptor/Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Dual Agonists 277 20.7 GLP-1 Receptor/Glucagon Receptor/GIP Receptor Triple Agonists 279 20.8 Further Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the One-pharmacophore Approach 280 20.9 Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the Two-pharmacophore Approach 282 20.10 Conclusion 284 References 284 21 The SOSA Approach to Drug Discovery 289 21.1 Introduction 289 21.2 Definition, Rational, and Concept of the SOSA Approach 290 21.3 Drugs in Other Drugs: Drug as Fragments 291 21.4 Old Drugs 292 21.5 The SOSA Approach and Analog Design 292 21.6 Patentability and Interference Risk of the SOSA Approach 293 21.7 Case Studies and Examples 296 21.8 Conclusion 312 Credit 313 References 313 Part D Polypharmacology, Classic Case Studies and Recent Research 319 22 Dual Inhibitors of CDK4/6 for Treating Cancer 321 22.1 Introduction 321 22.2 Selectivity Profile of Approved CDK4/6 Inhibitors 321 22.3 Clinical Experience with CDK4/6 Inhibitors 325 22.4 New Approaches and Agents for CDK4/6 Inhibition 330 22.5 Conclusion 331 Acknowledgment 332 References 332 23 Tapentadol, a Clinically Proven Analgesic with Two Mechanisms 339 23.1 Introduction 339 23.2 The Discovery of Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol 339 23.3 Pharmacokinetics of Tapentadol 342 23.4 The Polymorphic Forms of Tapentadol Hydrochloride 343 23.5 Pharmaceutical Salts of Tapentadol 344 23.6 Synthesis Routes to Tapentadol Hydrochloride 354 23.7 The Pharmacological Profile of Tapentadol as a Multiple Ligand for the Treatment of Several Types of Pain 356 23.8 Summary 363 References 363 24 Thalidomide – From a Banned Drug to Molecular Glues, PROTACs, and New Concepts in Drug Discovery 367 24.1 Introduction 367 24.2 Thalidomide History: From Tragedy to Therapeutic Revival 367 24.3 Polypharmacology of Thalidomide and its Derivatives 370 24.4 Structural Understanding of the Mechanisms of Action of CELMoDs 374 24.5 Challenges and Future Perspectives in the Development of CELMoDs 377 24.6 Conclusions 379 References 379 25 The Polypharmacology of Cariprazine and its Implications to Clinical Indications 385 25.1 Introduction 385 25.2 Structure and Binding 386 25.3 The Role of the Primary and Secondary Pharmacophore in Binding and Selectivity 387 25.4 Cariprazine–Functional Profile, Polypharmacology, and Functional Selectivity 389 25.5 In Vivo Profile of Cariprazine 390 25.6 Cariprazine in Clinical Practice 393 25.7 Conclusions 395 References 396 26 Multi-Targeted Antivirals 405 26.1 Multi-Target Inhibitors Targeting Both SARS-CoV-2 and Host Proteins 405 26.2 Multi-Target Inhibitors Directly Targeting SARS-CoV- 2 411 26.3 Summary and Prospect 417 Acknowledgments 418 References 418 27 Multi-target Antimalarials as a Strategy to Reduce Resistance Risk 423 27.1 Introduction 423 27.2 Next-generation Antimalarials 424 27.3 Resistance Risk as a Criterion for the Prioritization of New Molecules and Targets 424 27.4 Polypharmacology in Malaria Drug Discovery 426 27.5 Concluding Remarks and the Way Forward 432 References 432 28 Multi-target Compounds for Tuberculosis 437 28.1 Tuberculosis and the Problem of Antimicrobial Resistance 437 28.2 Polypharmacology to Fight M. tuberculosis Antimicrobial Resistance 438 28.3 Multitarget Compounds Against TB 439 28.4 Multitarget Compounds Against TB-HIV Co-infection 443 28.5 Conclusions 445 References 445 29 Dual-acting HIV Inhibitors 451 29.1 Introduction 451 29.2 HIV and Hepatitis Viruses Co-infections 451 29.3 Compounds with Dual Activity Against HIV and EV-A 71 456 Acknowledgement 458 References 458 30 Multi-kinase Inhibitors for the Treatment of Pancreatic Cancer 463 Acknowledgements 467 References 467 Index 469
Jürgen Bajorath
Eric A.G. Blomme, Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Terry R. Van Vleet, and Andy Vo
Dimitar Yonchev
Sonia Roberts and Helen L. Lightfoot
Jens-Uwe Peters
Stephan Kirchner
Ian M. Bell and Armando A. Lagrutta
Cristian Nogales, Zina Piper, Zeinab Mamdouh, and Mayra Pacheco Pachado
Balaguru Ravikumar, Anna Cichońska, Navriti Sahni, Tero Aittokallio, and Rayees Rahman
Lynn L. Silver
Yang Zhou, Shujing Xu, Dang Ding, Kai Tang, Xinyong Liu, Meehyein Kim, and Peng Zhan
Tiffany Schwasinger-Schmidt
Felix F. Lillich, Samaneh Goorani, Ewgenij Proschak, and John D. Imig
Elisa Uliassi, Anna M. Pasieka, Eleonora Diamanti, and Maria Laura Bolognesi
Axel Helmstaedter
Dayong Shi and Xiangqian li
Maedeh Darsaraee, Sacha Javor, and Jean-Louis Reymond
Arsenio Nueda
Alberto Ambesi-Impiombato, Lee McDermott, Alan Lars Pehrson, and Daniela Brunner
Martin Bossart and Gerhard Hessler
Norbert Handler, Michal Poznik, and Helmut Buschmann
Peter L. Toogood
Thomas Christoph, Helmut Buschmann, Norbert Handler, and Michal Poznik
Junichi Yamamoto, Hiroshi Handa, and Yuki Yamaguchi
Attila Egyed, Dóra J. Kiss, and György M. Keserű
Bing Ye, Letian Song, Meehyein Kim, Shenghua Gao, Peng Zhan, and Xinyong Liu
Lauren B. Coulson and Kelly Chibale
Giovanni Stelitano, Mario Cocorullo, and Laurent R. Chiarelli
María-José Camarasa, Ana-Rosa San-Félix, and Sonia de Castro
Paul Dent and Andrew Poklepovic
Subject Areas: Chemistry [PN]
