Polypharmacology
Description
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:
- Molecular properties and structural motifs in pharmacological promiscuity, covering lipophilicity, molecular weight, and other parameters
- Kinase liabilities in early drug discovery, covering core kinases driving the cell division cycle and consequences of interference, and cell cycle checkpoints controlling cell division
- Treatment of major depressive disorder, covering tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin and norepinephrine reuptake inhibitors
- Trends in the field, such as novel antipsychotics, standardization of screening tools, and the SmartCube System®, as well as lessons from history
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.
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Jens-Uwe Peters, PhD is a Director of Medicinal Chemistry at Skyhawk Therapeutics, and he previously worked at Idorsia Pharmaceuticals and Roche. He has extensive experience with drug discovery projects and safety profiling. He edited the book Polypharmacology in Drug Discovery (Wiley 2012).
Content
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 Cichonska, 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 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
Peter L. Toogood
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
Thomas Christoph, Helmut Buschmann, Norbert Handler, and Michal Poznik
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
Junichi Yamamoto, Hiroshi Handa, and Yuki Yamaguchi
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
Attila Egyed, Dóra J. Kiss, and György M. Keseru
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
Bing Ye, Letian Song, Meehyein Kim, Shenghua Gao, Peng Zhan, and Xinyong Liu
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
Lauren B. Coulson and Kelly Chibale
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
Giovanni Stelitano, Mario Cocorullo, and Laurent R. Chiarelli
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
María-José Camarasa, Ana-Rosa San-Félix, and Sonia de Castro
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
Paul Dent and Andrew Poklepovic
Acknowledgements 467
References 467
Index 469
