Polypharmacology in Drug Discovery [NOOK Book]

Overview

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 ...

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Polypharmacology in Drug Discovery

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Overview

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:

  • Covers the two-sided nature of polypharmacology—its contribution to adverse drug reactions and its benefit in certain therapeutic drug classes

  • Addresses the important topic of polypharmacology in drug discovery, a subject that has not been thoroughly covered outside of scattered journal articles

  • Overviews state-of-the-art approaches and developments to help readers understand concepts and issues related to polypharmacology

  • 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 discoveryprojects.

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Editorial Reviews

Doody's Review Service
Reviewer: Rachel R Chennault, PhD (American College of Clinical Pharmacy)
Description: This book examines the emerging polypharmacological philosophy in drug discovery research (a single compound with multiple targets), challenging the current "one-drug-one-target" approach to drug discovery. It reviews the necessary considerations during safety profiling to assess the delicate balance between promiscuous drugs' therapeutic efficacies (benefits) and adverse drug reactions, or ADRs (risks).
Purpose: Historically, researchers have sought to develop highly selective drugs in an effort to minimize ADRs due to unintended off-target effects. However, this book educates readers about the unique advantages that polypharmacological therapies have over single-target compounds, particularly in treating complex disease states, where either multiple factors contribute to pathogenicity or drug resistance arises.
Audience: This book is intended to guide drug development researchers in academic and industry sectors alike through the inherent challenges of the polypharmacological approach, with in-depth discussion of the benefits and dangers of promiscuous ligands and targets. Additionally, as the chapters of this book are authored by highly qualified experts in the pharmaceutical sciences, pharmacology students will benefit from the discussion of the fundamental concepts of polypharmacology.
Features: Organized into four distinct sections, the book begins with a discussion of the safety concerns due to off-target activities, as well as rationale for considering these activities early in the drug discovery process. The next section describes the advantages of a polypharmacological approach to drug development over a single-target philosophy by targeting networks of disease-related pathways, citing therapies for psychiatric diseases, cancer, bacterial infections, and epilepsy. The third section reviews state-of-the-art interdisciplinary approaches to promiscuous drug development that combine computational modeling with in vitro and in vivo screening assays. Finally, the last section contains various case studies with real examples of currently marketed multitargeted compounds that modulate diverse networks in the treatment of complex, polygenic diseases.
Assessment: To date, the discussion surrounding polypharmacology has been limited to a small number of journal articles and a single chapter in Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs, Barratt and Frail Wiley-Blackwell, 2012). This book is a unique and comprehensive resource for navigating the field of promiscuous drug development and research.
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Product Details

  • ISBN-13: 9781118098134
  • Publisher: Wiley
  • Publication date: 1/20/2012
  • Sold by: Barnes & Noble
  • Format: eBook
  • Edition number: 1
  • Pages: 464
  • File size: 9 MB

Meet the Author

Jens-Uwe Peters, PhD, works in the Medicinal Chemistry Department at F. Hoffmann-La Roche. In his ten years at Roche, he has been involved in numerous drug discovery projects, has contributed to Early Safety Profiling initiatives, and has researched opportunities for polypharmacological drug discovery. Dr. Peters is author or coauthor on twenty-six journal papers and is named on twenty-two patents.

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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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