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Drug Target Informatics DrugDrug TargetTarget InformaticsInformatics … and answers to the questions: What is a drug target? How many such targets are there?*) Tudor I. Oprea Division of Biocomputing University of New Mexico School of Medicine [email protected] *) P. Imming, C. Sinning, A. Meyer, Nature Rev. Drug Discov 2006, 5: 821-834 *) J. Overington, B. Al-Lazikani, A.L. Hopkins, Nature Rev. Drug Discov 2006, 5: 993-996 Drug Discovery Informatics 2 The University of New Mexico Copyright © Tudor I. Oprea, 2008. All rights reserved Division of BIOCOMPUTING OutlineOutline • Phases of Drug Discovery - recap • Target Informatics: How many Drug Targets? – Examples by Drug – Examples by Target Class • Oral Drug Targets: Can Literature be corrected? • Errors in Drug Target Informatics – What X-ray crystallographers won’t tell you • The Physical Basis of the Rule of Five TargetTarget IdentificationIdentification inin PreclinicalPreclinical DiscoveryDiscovery Target Hit Lead Lead Clinical Identification Identif. Identif. optim. Candidate Human genetics Mouse genetics Identification Validation Production The key in target identification is mass production of pure protein for structural studies ModernModern TechnologiesTechnologies inin PreclinicalPreclinical DiscoveryDiscovery Target Hit Lead Lead Clinical Identification Identif. Identif. optim. Candidate Synthetic Compounds Natural Products High Throughput Synthesis and Screening ModernModern TechnologiesTechnologies inin PreclinicalPreclinical DiscoveryDiscovery Target Hit Lead Lead Clinical Identif Identif. Identif. optim. Candidate R2 R1 N R3 " " R4 Combinatorial & Medicinal Toxicogenomics Chemistry ModernModern TechnologiesTechnologies inin PreclinicalPreclinical DiscoveryDiscovery Target Hit Lead Lead Clinical Identif Identif. Identif. optim. Candidate NH2 O N O H O O Structure-based Drug Design Transgenic animals Zanamivir (inhaled; Relenza®) Clinically relevant disease models first anti-influenza drug (1999) Study metabolism & toxicology in Oseltamivir (orally available prodrug, “human”-ized conditions Tamiflu ®) launched in 2001 TheThe AttritionAttrition RateRate inin DrugDrug DiscoveryDiscovery Increased knowledge and value HTS Hits HTS Actives HTS Drug Candidates Lead Series Drug re ailu of f sk 1,000,000 d ri ease Incr 2,000 1,200 50-200 1 0.1 Increased experimental error rate TheThe MolecularMolecular PharmacopoeiaPharmacopoeia DrugDrug TargetsTargets && DisDis--easeease • Literature estimates the number of drug targets between 5,000 (high estimate) to 500 (targets hit by current drugs) – Definition: A target is a macro-molecular structure (defined by at least a molecular mass) that undergoes a specific interaction with therapeutics (chemicals administered to treat or diagnose a disease). The target-drug interaction results in clinical effect(s). – Imming, Sinning & Meyer considered the ’intended’ (not side-effect) targets for drugs; validation in knock-out models - a plus; receptor (ant)agonism, enzyme inhibition were also considered proof; 1-3 targets/drug were considered [was this OK?!]. – Overington, Al-Lazikani & Hopkins considered protein targets for FDA- approved drugs only (~1200 drugs from the Orange Book). They did make allowances for ”non-intended” drug targets for, e.g., ritonavir – an HIV- protease inhibitor given in combination with other such inhibitors because it slows down their metabolism via CYP3A4 inhibition (thus CYP3A4 was considered a drug target for ritonavir). [this was better]. • Part of the problem: there is no “right” definition for health (e.g, free from dis-ease). In the case of sickness, do we “cure”, do we “treat” patients, or do we heal them? AspirinAspirin –– thethe ““firstfirst drugdrug”” O O • COX-1; Prostaglandin G/H synthase 1 O • COX-2; Prostaglandin G/H synthase 2 Acts as suicide inhibitor O • Platelet glycoprotein IIb of IIb/IIIa complex, or antigen CD41 Acts as competitive antagonist (μM inhibitor) (used as Baby Aspirin as antiaggregant) • Phospholipase A2 (PDB code 1OXR) Acts as competitive antagonist (μM inhibitor) History: Felix Hoffmann was believed to have developed aspirin for F. Bayer & Co., to help his rheumatic father. Arthur Eichengrün claimed in 1949 that the work had been done under his direction. Walter Sneader analyzed archival data from Bayer, as well as published material and concluded that Eichengrün's claim is valid. Acetylsalicylic acid was synthesised under Eichengrün's direction, and it would not have been introduced in 1899 without his intervention W. Sneader, British Medical Journal 2000, 321:1591–1594 IndomethacinIndomethacin –– anan antianti--inflammatoryinflammatory Anti-inflammatory; antipyretic; analgesic O • COX-1; Prostaglandin G/H synthase 1 (6.9) • COX-2; Prostaglandin G/H synthase 2 (6.05) • PLA2; Phospholipase A2 (8.0) acts as reversible, competitive inhibitor, with affinity in N O O O the sub-micromolar to nanomolar range • IL-1; interleukin 1 (6.5) acts as antagonist of PGE2 production (sub-μM) Cl (the above targets clearly related to inflammation) • Prostanoid DP2 receptor; GPR44 (7.5) Indomethacin is clinically used as tocolytic agent effective in preventing pre-term labour because it acts as full agonist on Prostanoid DP2 receptors DexamethasoneDexamethasone–– anotheranother antianti--inflammatoryinflammatory O Chiral O History: G.E. Arth discovered (at Merck) that 16α- O O substituted steroids are metabolically more stable. He H soon discovered that this also reduced the mineralo- cortoicoid, and enhanced the anti-inflammatory F H activity. Dexamethasone (1958) is more potent than O hydrocortisone, with a longer duration of action. Glucocorticoid; anti-inflammatory; diagnostic aid (Cushing Syndrome, depression) • Glucocorticoid receptor (8.28) – as competitive antagonist • IL-4; interleukin 4 (8.33) & IL-5; interleukin 5 (8.46) •TNF-α; tumor necrosis factor alpha (7.7); IFN-γ; interferon-gamma (10.0) (the above targets clearly related to inflammation) • Anti-Target (?): Mineralocorticoid receptor (7.48) • Anti-Target: PXR; Pregnane X receptor, as agonist Dexamethasone is used to treat inflammatory and autoimmune conditions, e.g., rheumatoid arthritis; and to counteract the development of brain edema; to prevent virilisation of a female fetus in congenital adrenal hyperplasia. Also used to counteract side-effects of antitumor treatment in cancer patients undergoing chemotherapy. AripiprazoleAripiprazole –– aa ““dirtydirty drugdrug”” exampleexample O • Target Meas Value Activity N •D2 Ki 0.34 nM partial agonist •D3 Ki 0.8 nM antagonist •D4 Ki 44 nM antagonist •5HT Ki 1.7 nM partial agonist O 1A •5HT2A Ki 3.4 nM antagonist •5HT2C Ki 15 nM antagonist •5HT7 Ki 39 nM antagonist •alphaAR Ki 57 nM antagonist N 1 •H1 Ki 61 nM antagonist N • 5HT reuptake Ki 98 nM antagonist • Aripiprazole is an antipsychotic and neuroleptic with Cl efficacy in schizophrenia and bipolar disorder. Its mechanism of action is unknown (as per FDA label), Cl although the above activities were observed. TamoxifenTamoxifen –– aa ““cleanclean drugdrug”” exampleexample OH • Estrogen receptor – intended CYP2D6, 2B6 2C9, 2C19, 3A drug target. TAM & metabolites antagonize dimer formation; ERα monomer + TAM can act HC3 CH3 HC3 CH3 N N as agonist (NFkB, AP-1) O CH3 O CH3 • GPR30 – 4-OH TAM agonist TAM 4OHTAM •ERRγ (estrogen-related CYP3A4/5 CYP3A4/5 response receptors, also class OH 3 NHRs) – 4OHTAM, CYP2D6 antagonist • Emopamil binding protein; 3β- HC CH HC CH 3 3 3 3 hydroxysteroid-Δ7-8 isomerase; NH NH O O cholestenol delta-isomerase (TAM, inhibitor) N-desmethylTAM Endoxifen • Type I sigma receptor (TAM & Desta, Z et al JPET 2004, 310:1062-1075 metab., antagonists) • PXR; Pregnane X receptor Tamoxifen is the gold standard “antiestrogen” therapy, used as the first line therapy in Estrogen positive breast cancers. Although its mechanism of action is “known” (as per FDA label), TAM has nanomolar affinity to all the above targets. AmantadineAmantadine –– aa ““simplesimple drugdrug”” exampleexample • D1 dopamine receptor agonist • D2 dopamine receptor agonist • N-methyl D-aspartate receptor subtype 2D (Glutamate [NMDA] receptor subunit epsilon 4) - antagonist at the NH2 Phencyclidine binding site Used in Parkinson’s disease • Antiviral against Influenza A virus by interfering with the viral M2 membrane ion channel; appears effective on all Influenza A viral strains • Antiviral against feline immunodeficiency virus Used as antiviral • Side effect 1: hERG (probably). Demonstrated to produce QT-prolongation (with risk for congenital long QT patients) • Side effect 2: anticholinergic-like effects (dry mouth, urinary retention, and constipation) – do not appear to be mediated by direct binding to cholinergic receptors AcyclovirAcyclovir –– UsingUsing ViralViral MachineryMachinery NH • DNA polymerase from Herpes Simplex Virus 2 H N • DNA polymerase from Herpes Zoster Virus N O In vitro and in vivo inhibitor against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus N N (VZV). O However, Acyclovir is a prodrug that requires conversion by viral thymidine kinases (TK), as encoded by HSV and VZV. These convert acyclovir into acyclovir OH monophosphate; this is further converted into diphosphate by cellular guanylate kinase ,and into triphosphate by cellular enzymes. • KITH_HHV1 (Q9QNF7) • KITH_HHV23 (P04407) • KITH_VZV7 (P14342) The above are SwissProt identifier for the 3 TK enzymes that are targeted by the prodrug ClorpromazineClorpromazine –– AnotherAnother antianti--Viral?Viral? Antiemetic; antipsychotic; neuroleptic Cl Clorpromazine
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