Polypharmacology in Drug Discovery
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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
2.2 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
3.1 Introduction: pharmacological promiscuity in the history of drug discovery.
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
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
5.2 Screening methods.
5.3 Structural insights into the interaction between drugs and CV ion channels.
5.4 Medicinal Chemistry approaches.
6 Prediction of side effects based on fingerprint profiling and data mining
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.
6.7 Patterns of activity.
6.8 Integrating function profile data with traditional pharmacological binding data.
6.9 Analysis of the antifungal tioconazole.
Part B: Polypharmacology – an opportunity for drug discovery.
7 Polypharmacological drugs – "magic shotguns" for psychiatric diseases
Wesley K. Kroeze and Bryan L. Roth
7.3 The discovery and extent of promiscuity among psychiatric drugs.
7.4 Why are so many psychiatric drugs promiscuous?
8 Polypharmacological kinase inhibitors: new hopes for the therapy of cancer
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
9.2 Classical antibacterial polypharmacology.
9.3 New approaches to multi-targeted single pharmacophores.
9.4 Synthetic lethals.
9.5 Hybrid molecules.
10 A "magic shotgun" perspective on anticonvulsant mechanisms
Matt T. Bianchi and Kathy Chuang
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.
11 Selective Optimization of Side Activities (SOSA): a promising way for drug discovery
Thierry Langer and Camille-Georges Wermuth
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.
11.8 Computer-assisted design using pharmacophores.
Part C: Selected approaches to polypharmacological drug discovery
12 Selective multi-targeted drugs
12.2 Lead Generation.
12.3 Lead optimization.
12.4 Case studies.
13 Computational multitarget drug discovery
Jeremy A. Horst, Adrian Laurenzi, Brady Bernard and Ram Samudrala
13.2 The pharmacologic hunt of yesteryear.
13.3.Established technological advancements.
13.4.Computational drug discovery.
13.5.Recent technical improvements.
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.
15 Multicomponent Therapeutics
Alexis A. Borisy, Grant R. Zimmermann and Joseph Lehár
15.2 Drug synergies are statistically more context dependent.
15.3 How a synergistic mechanism can lead to therapeutic selectivity.
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.
17.1 Definition and diagnosis of schizophrenia.
17.2 Etiology and pathophysiology of schizophrenia.
17.4 Medical practice and treatment options.
17.5 Case studies.
18 Triple Uptake Inhibitors ("Broad Spectrum" Antidepressants)
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.
20 Drug research leading to imatinib and beyond to nilotinib
Paul W. Manley and Jürg Zimmermann
20.2 Historical background.
20.3 BCR-ABL1 as the molecular target for CML therapy.
21 Towards antimalarial hybrid drugs
22 Multitarget drugs for the treatment of Alzheimer’s disease
Andrea Cavalli and Maria Laura Bolognesi
22.2 Case studies.
22.3 Conclusions and perspectives.
23 Carbonic anhydrases: off-targets, add-on activities, or emerging novel targets?
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.