An essential outline of the main facets of polypharmacology in drug discovery research
Extending drug discovery opportunities beyond the "one drug, one target" philosophy, a polypharmacological approach to the treatment of complex diseases is emerging as a hot topic in both industry and academic research. Polypharmacology in Drug Discovery presents an overview of the various facets of polypharmacology and how it can be applied as an innovative concept for developing medicines for treating bacterial infections, epilepsy, cancer, psychiatric disorders, and more. Filled with a collection of instructive case studies that reinforce the material and illuminate the subject, this practical guide:
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Covers the two-sided nature of polypharmacologyits contribution to adverse drug reactions and its benefit in certain therapeutic drug classes
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Addresses the important topic of polypharmacology in drug discovery, a subject that has not been thoroughly covered outside of scattered journal articles
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Overviews state-of-the-art approaches and developments to help readers understand concepts and issues related to polypharmacology
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Fosters interdisciplinary drug discovery research by embracing computational, synthetic, in vitro and in vivo pharmacological and clinical aspects of polypharmacology
A clear road map for helping readers successfully navigate around the problems involved with promiscuous ligands and targets, Polypharmacology in Drug Discovery provides real examples, in-depth explanations and discussions, and detailed reviews and opinions to spark inspiration for new drug discovery projects.
Table of Contents
List of contributors.Preface.
Introduction: the case for polypharmacology
Andrew L. Hopkins
Part A: Polypharmacology – a safety concern in drug discovery.
1 The relevance of off-target polypharmacology
Bruce D. Car
2 Screening for safety-relevant off-target activities
Laszlo Urban, Steven Whitebread, Jacques Hamon, Dmitri Mikhailov and Kamal Azzaoui
2.1 Introduction.
2.2 General aspects.
2.3 Selection of off-targets.
2.4 In silico approaches to off-target profiling.
2.5 Summary and conclusions.
3 Pharmacological promiscuity and molecular properties
Jens-Uwe Peters
3.1 Introduction: pharmacological promiscuity in the history of drug discovery.
3.2 Lipophilicity.
3.3 Molecular weight.
3.4 Ionisation state.
3.5 Other molecular descriptors and structural motifs.
3.6 Implications for drug discovery.
4 Kinases as antitargets in genotoxicity
Stephan Kirchner
4.1 Protein Kinases and inhibitor-binding sites.
4.2 Cyclin-Dependent Kinases (CDKs) controlling unregulated cell proliferation.
4.3 Mitotic kinases as guardians protecting cells from aberrant chromosome segregation.
5 Activity at cardiovascular ion channels: a key issue for drug discovery
Ian M. Bell, Mark T. Bilodeau and Armando A. Lagrutta
5.1 Introduction.
5.2 Screening methods.
5.3 Structural insights into the interaction between drugs and CV ion channels.
5.4 Medicinal Chemistry approaches.
5.5 Conclusion.
6 Prediction of side effects based on fingerprint profiling and data mining
Jacques Migeon
6.1 Introduction to BioPrint.
6.2 The pharmacological fingerprint.
6.3 Antidepressant example.
6.4 Profile similarity at non-therapeutic targets.
6.5 Interpreting the polypharmacology profile.
6.6 Methods.
6.7 Patterns of activity.
6.8 Integrating function profile data with traditional pharmacological binding data.
6.9 Analysis of the antifungal tioconazole.
6.10 Conclusions.
Part B: Polypharmacology – an opportunity for drug discovery.
7 Polypharmacological drugs – "magic shotguns" for psychiatric diseases
Wesley K. Kroeze and Bryan L. Roth
7.1 Introduction.
7.2 Definition.
7.3 The discovery and extent of promiscuity among psychiatric drugs.
7.4 Why are so many psychiatric drugs promiscuous?
7.5 Conclusions.
8 Polypharmacological kinase inhibitors: new hopes for the therapy of cancer
Annalisa Petrelli
8.1 Targeted therapies: a new era in the treatment of cancer.
8.2 The single-targeted therapy.
8.3 From single to multi-targeted drugs in cancer therapy.
8.4 Polypharmacology kinase inhibitors in clinical practice and under development.
8.5 Concluding remarks.
9 Polypharmacology as an emerging trend in antibacterial discovery
Lynn L. Silver
9.1 Introduction.
9.2 Classical antibacterial polypharmacology.
9.3 New approaches to multi-targeted single pharmacophores.
9.4 Synthetic lethals.
9.5 Hybrid molecules.
9.6 Conclusions.
10 A "magic shotgun" perspective on anticonvulsant mechanisms
Matt T. Bianchi and Kathy Chuang
10.1 Introduction.
10.2 Anticonvulsant mechanism.
10.3 Defining promiscuity.
10.4 Promiscuity: lessons from endogenous signaling.
10.5 Promiscuity: lessons from anticonvulsant electrophysiology.
10.6 Use of anticonvulsants in disorders other than epilepsy.
10.7 Experimental and theoretical support for a "Magic Shotgun" approach.
10.8 Current multi-target strategies.
10.9 Practical considerations.
10.10 Conclusion.
11 Selective Optimization of Side Activities (SOSA): a promising way for drug discovery
Thierry Langer and Camille-Georges Wermuth
11.1 Introduction.
11.2 Definition and principle.
11.3 Rationale of SOSA.
11.4 Establishing the SOSA approach.
11.5 A successful example of the SOSA approach.
11.6 Other examples of SOSA switches.
11.7 Discussion.
11.8 Computer-assisted design using pharmacophores.
11.9 Conclusions.
Part C: Selected approaches to polypharmacological drug discovery
12 Selective multi-targeted drugs
Richard Morphy
12.1 Introduction.
12.2 Lead Generation.
12.3 Lead optimization.
12.4 Case studies.
12.5 Summary.
13 Computational multitarget drug discovery
Jeremy A. Horst, Adrian Laurenzi, Brady Bernard and Ram Samudrala
13.1 Introduction.
13.2 The pharmacologic hunt of yesteryear.
13.3.Established technological advancements.
13.4.Computational drug discovery.
13.5.Recent technical improvements.
13.6.Emerging concepts.
13.7 Summary.
14 Behavior-based screening as an approach to polypharmacological ligands
Dani Brunner, Vadim Alexandrov, Barbara Caldarone, Taleen Hanania, David Lowe, Jeff Schneider and Jayaraman Chandrasekhar
14.1 The Challenges of CNS Drug Discovery.
14.2 In vivo high throughput screening.
14.3 Screening libraries of compounds.
14.4 Relationship between molecular properties and in vivo CNS activity.
14.5 Following screening hits in secondary assays.
14.6 Potential therapeutic value of dual adenosine compounds.
14.7 Summary.
15 Multicomponent Therapeutics
Alexis A. Borisy, Grant R. Zimmermann and Joseph Lehár
15.1 Introduction.
15.2 Drug synergies are statistically more context dependent.
15.3 How a synergistic mechanism can lead to therapeutic selectivity.
15.4 Discussion.
Part D: Case studies
16 The discovery of sunitinib as a multitarget treatment of cancer
Catherine Delbaldo, Camelia Colichi, Marie-Paule Sablin, Chantal Dreyer, Bertrand Billemont, Sandrine Faivre and Eric Raymond
16.1 A brief introduction to tumor angiogenesis.
16.2 The discovery of sunitinib: from drug design to first evidences of clinical activity.
16.3 Pharmacology of sunitinib.
16.4 Safety of sunitinib.
16.5 Activity of Sunitinib.
16.6 Surrogate imaging techniques to capture vascular changes.
16.7 Surrogate biomarkers.
16.8 Conclusion.
17 Antipsychotics
Claus Riemer
17.1 Definition and diagnosis of schizophrenia.
17.2 Etiology and pathophysiology of schizophrenia.
17.3 Epidemiology.
17.4 Medical practice and treatment options.
17.5 Case studies.
17.6 CATIE.
17.7 Conclusions.
18 Triple Uptake Inhibitors ("Broad Spectrum" Antidepressants)
Phil Skolnick
18.1 Introduction.
18.2 What is the rationale for developing triple uptake inhibitors as antidepressants?
18.3 Preclinical data.
18.4 Clinical data.
18.5 Concluding remarks.
19 Therapeutic potential of small molecules modulating the cyclooxygenase and 5-lipoxygenase pathway
Stefan Laufer and Wolfgang Albrecht
19.1 Targets of the eicosanoid pathway.
19.2 Rationale for development of dual inhibitors of the cyclooxygenase and 5-lipoxygenase pathway.
19.3 Dual inhibitors of the cyclooxygenase and 5-lipoxygenase pathway.
19.4 Development of Licofelone.
19.5 Conclusions.
20 Drug research leading to imatinib and beyond to nilotinib
Paul W. Manley and Jürg Zimmermann
20.1 Introduction.
20.2 Historical background.
20.3 BCR-ABL1 as the molecular target for CML therapy.
21 Towards antimalarial hybrid drugs
Bernard Meunier
22 Multitarget drugs for the treatment of Alzheimer’s disease
Andrea Cavalli and Maria Laura Bolognesi
22.1 Introduction.
22.2 Case studies.
22.3 Conclusions and perspectives.
23 Carbonic anhydrases: off-targets, add-on activities, or emerging novel targets?
Claudiu Supuran
23.1 Introduction.
23.2 Carbonic anhydrase inhibition.
23.3 Topiramate and zonisamide, antiepileptics with potent antiobesity action.
23.4 Sulfonamide coxibs with antitumor activity due to CA IX/XII inhibition.
23.5 Sulfamates with steroid sulfatase and carbonic anhydrase inhibitory action as anticancer agents in clinical development.
23.6 Lacosamide, an antiepileptic with a strange binding mode to Cas.
23.7 The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian CA isoforms.
23.8 Conclusions.
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