List of Contributors xvii Preface xxiii 1 Introduction 1 Jürgen Bajorath 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 Eric A.G. Blomme, Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Terry R. Van Vleet, and Andy Vo 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 Dimitar Yonchev 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 Sonia Roberts and Helen L. Lightfoot 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 Jens-Uwe Peters 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 Stephan Kirchner 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 Ian M.

Bell and Armando A. Lagrutta 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 Cristian Nogales, Zina Piper, Zeinab Mamdouh, and Mayra Pacheco Pachado 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 Balaguru Ravikumar, Anna Cichooska, Navriti Sahni, Tero Aittokallio, and Rayees Rahman 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 Lynn L. Silver 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 Yang Zhou, Shujing Xu, Dang Ding, Kai Tang, Xinyong Liu, Meehyein Kim, and Peng Zhan 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 Tiffany Schwasinger-Schmidt 12.1 Introduction 165 12.2 Multitargeted Antidepressants 166 12.

3 Conclusions 170 References 171 13 Multi-target Drugs to Treat Metabolic Diseases 175 Felix F. Lillich, Samaneh Goorani, Ewgenij Proschak, and John D. Imig 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 Elisa Uliassi, Anna M. Pasieka, Eleonora Diamanti, and Maria Laura Bolognesi 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 Axel Helmstaedter 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 Dayong Shi and Xiangqian li 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 Maedeh Darsaraee, Sacha Javor, and Jean-Louis Reymond 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 Arsenio Nueda 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 Alberto Ambesi-Impiombato, Lee McDermott, Alan Lars Pehrson, and Daniela Brunner 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 Martin Bossart and Gerhard Hessler 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 Norbert Handler, Michal Poznik, and Helmut Buschmann 21.1 Introduction 289 21.2 Definit.