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Lecture 8: Computational Drug Target Identification

Lecture 8: Computational Drug Target Identification. Y.Z. Chen Department of Computational Science National University of Singapore E-mail: yzchen@cz3.nus.edu.sg Web-page: http://www.cz3.nus.edu.sg/~yzchen/. Outline. Potential Application :

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Lecture 8: Computational Drug Target Identification

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  1. Lecture 8: Computational Drug Target Identification Y.Z. Chen Department of Computational Science National University of Singapore E-mail: yzchen@cz3.nus.edu.sg Web-page: http://www.cz3.nus.edu.sg/~yzchen/

  2. Outline • Potential Application: • Unknown and secondary therapeutic targets of drugs, leads, natural products. • Targets related to toxicity, side-effect, delivery. • Ligand-protein interactions involved in pathways. • Methodology: • Ligand-protein inverse docking • Tests: • Known targets for therapeutics, toxicity and side effect. Y.Z. Chen, National University of Singapore E-mail: yzchen@cz3.nus.edu.sgWeb-page: http://www.cz3.nus.edu.sg/~yzchen/

  3. Why protein targets?Novel or Unknown Therapeutic Targets Nature 1998, 396:15

  4. Why protein targets?Toxicity, side effect, pharmacokinetics and pharmacogenetics Annu. Rev. Pharmacol Toxicol 2000, 40:353-388 1997, 37:269-296 Pharmacological Rev. 2000, 52:207-236

  5. Why protein targets? Towards the prediction of side effect, toxicity, pharmacokinetics in early stages of drug discovery • Most drug candidates fail to reach market • Pharmacokinetics, side effect and toxicity are the main reason. • Large portion of money ($350 million per drug) and time (6-12 years for a drug) has been wasted on failed drugs. Drug Discov Today 1997; 2:72 Drug Candidates in Different Stages of Development Majority of Them Fail to Reach Market Clin Pharmacol Ther. 1991; 50:471

  6. Why protein targets?Drugs from Natural Products From natural products to therapeutic drugs TIPS, May 1999, 20:190 Traditional medicines Pharmacology & Therapeutics 2000, 86:191 • Screening or extraction of bioactive compounds • Mechanism and standardization • Further development

  7. Drug targets and new drug discoveryDrugs from Traditional Medicines • Mixture of multiple herbs etc. • Therapeutic action + maintaining and restoring balance: Mutual accentuation, mutual enhancement, mutual counteraction, mutual suppression, mutual antagonism, mutual incompatibility • Multiple targets: therapeutic effect, symptom treatment, toxicity modulation, drug delivery, harmonization Pharmacology & Therapeutics 2000, 86:191

  8. Why searching protein targets of a molecule?Applications in pathways EGF Pathway From Signaling Pathway Database http://www.grt.kyushu-u.ac.jp/spad/

  9. Strategy Proteins 2001;43:217 Science 1992;257: 1078

  10. Feasibility Proteins • Database: >12,000 3D structures in PDB. • Protein diversity: 17% in PDB with unique sequence. • Advances in structural genomics: 10,000 unique proteins within 5 years. Ann. Rev. Biophys. Biomol. Struct. 1996; 25:113 Nature Struct. Biol. 1998; 5:1029 Method • Ligand-protein docking docking algorithms capable of finding binding conformations. Proteins. 1999; 36:1 Proteins 2001; 43:217 Additional information • Rapid accumulation of knowledge in proteomics, pathways, protein functions (functional genomics). Computer resources • Increasing power and decreasing cost (Linux PC, Multi-processor Machine)

  11. Automated Protein Targets Identification Software INVDOCK

  12. INVDOCK Cavity Models HIV-1 Protease

  13. INVDOCK Cavity Models Estrogen Receptor

  14. Energy Functions • Chemical bonds • Hydrogen bonding • van der Waals interactions • Electrostatic interactions • Empirical solvation free energy V = Vbonds + H bonds [ V0 (1-e-a(r-r0) )2 - V0 ] + non bonded [ Aij/rij12 - Bij/rij6 + qiqj /r rij] + atoms iDsi Ai

  15. Description of Docking Quality Molecule Docked Protein PDB Id RMSD Energy Match Indinavir HIV-1 Protease 1hsg 1.38 -70.25 Match Xk263 Of Dupont Merck HIV-1 Protease 1hvr 2.05 -58.07 Match Vac HIV-1 Protease 4phv 0.80 -88.46 One end match, the other in slightly different orientation Folate Dihydrofolate Reductase 1dhf 2.41 -63.02 Match 5-Deazafolate Dihydrofolate Reductase 2dhf 1.48 -65.49 Match Estrogen Estrogen Receptor 1a52 1.30 -45.86 Match 4-Hydroxytamoxifen Estrogen Receptor 3ert 0.97 -55.15 Match Guanosine-5'-[B,G-Methylene] Triphosphate H-Ras P21 121p 0.94 -80.20 Match Glycyl-*L-Tyrosine Carboxypeptidase A a 3cpa 2.19 -44.84 INVDOCK Testing Results

  16. Compound Potential Targets Identified Experimentally Confirmed Experimentally Implicated 4H-Tamoxifen 17 4 4 Aspirin 52 4 16 Vitamin C 46 4 9 Vitamin E 26 2 11 INVDOCK Testing Results

  17. PDB Putative Protein Target Experimental Finding Target Status Clinical Implication Ref 1a52 Estrogen Receptor Drug target Confirmed Treatment of breast cancer 36 1akz Uracil-DNA Glycosylase 1ayk Collagenase Inhibited activity Confirmed Tumor cell invasion and cancer metastasis 38 1az1 Aldose Reductase 1bnt Carbonic Anhydrase 1boz Dihydrofolate Reductase Decreased level Combination therapy for cancer 43 1dht, 1fdt 17b -Hydroxysteroid Dehydrogenase Inhibitor Confirmed Promotion of tumor regression 39 1gsd, 3ljr Glutathione Transferase A1-1, Glutathione S-Transferase Suppressed enzyme and activity Genotoxicity and carcinogenicity 41 INVDOCK Identified Protein TargetsFor an Anticancer Drug Tamoxifen

  18. 1mch Immunoglobulin l Light Chain Temerarily enhanced Ig level Modulation of immune response 44 1p1g Macrophage Migration Inhibitory factor 1ulb Purine Nucleoside Phosphorylase 1zqf DNA Polymerase b 2nll Retinoic Acid Receptor 1a25 Protein Kinase C Inhibition Confirmed Anticancer 37 1aa8 D-Amino Acid Oxidase 1afs 3a -Hydroxysteroid Dehydrogenase Effect on androgen induced activity Hepatic steroid metabolism 42 1pth Prostaglandin H2 Synthase-1 Direct inhibition Confirmed Prevention of vasoconstriction 40 INVDOCK Identified Protein TargetsFor an Anticancer Drug Tamoxifen

  19. Compound Number of experimentally confirmed or implicated toxicity targets Number of toxicity targets predicted by INVDOCK Number of toxicity targets missed by INVDOCK Number of toxicity targets without 3D structure or involving covalent bond Number of INVDOCK predicted toxicity targets without experimental finding Aspirin 15 9 2 4 2 Gentamicin 17 5 2 10 2 Ibuprofen 5 3 0 2 2 Indinavir 6 4 0 2 2 Neomycin 14 7 1 6 6 Penicillin G 7 6 0 1 8 Tamoxifen 2 2 0 0 4 Vitamin C 2 2 0 0 3 Total 68 38 5 25 29 INVDOCK Testing on Toxicity Targets

  20. PDB Protein Experimental Finding Target Status Toxicity/Side Effect Ref 1a42 Carbonic anhydrase II Activate enzyme activity that may lead to increase in plasma bicarbonate concentration. Implicated Metabolic alkalosis (hypoventilation). Puscas I 1a6a HLA-DR3 Change in HLA level Implicated Aspirin-induced asthma Dekker JW 1a7c Plasminogen activator inhibitor Tissue-dependent response of protein. Implicated Hypertension, thrombolysis Smokovitis A 1d6n Hypoxanthine-guanine phosphoribosyltransferase Excess uric acid in serum* 1hdy Alcohol dehydrogenase Inhibition of activity Confirmed Increased blood alcohol level Gentry RT Toxicity and side effect targets of Aspirin identified from INVDOCK search of protein database

  21. 1hdy Alcohol dehydrogenase Inhibition of activity Confirmed Increased blood alcohol level Gentry RT 1hiq Insulin Tissue insensitivity to insulin Implicated Impaired glucose metabolism in insulin-sensitive cells. Newmann WP 1hmr Fatty acid binding protein Increased binding capacity and protein content. Implicated Effect on peroxisomal beta oxidation activity. Kawashima Y 1mch Immunoglobulin lambda light chain Ig reactivities Implicated Allergic reaction to aspirin. Zhu DX 1pah Phenylalanine hydroxylase Phenylketonurea* 2ant Antithrombin Irreversibly acetylate antithrombin. Confirmed Blood coagulation, thrombolysis. Villanueva GB 2hdh L-3-hydroxyacyl CoA dehydrogenase Reversible inhibition of enzyme activity. Confirmed Effect on Reye's syndrome patients. Glasgow JF Toxicity and side effect targets of Aspirin identified from INVDOCK search of protein database

  22. Chinese Natural Product Number of Identified Therapeutic Targets Number Confirmed or Implicated Therapeutic Targets by experiment Number of Identified Toxicity/Side effect Targets Number Confirmed or Implicated Toxicity/Side Effect Targets by experiment Acronycine 3 1 4 - Allicin 5 2 1 1 Baicalin 14 4 6 - Catechin 17 12 5 - Camptothecine 9 6 3 2 Dicoumarin 7 1 3 1 Emodin 6 3 5 1 Genistin 22 7 12 1 Molecular targets of Chinese natural products

  23. Putative and known therapuetic targets of Camptothecine identified from INVDOCK search of human and mammalian proteins PDB Protein Experimental Finding Target Status Theraputic Effect Ref 1ads Aldose Reductase Diabetes treatment 2gss Glutathione S-Transferase p1-1 Increases intracellular glutathione Implicated Enhance radical scavenging activities that may useful in cancer treatment Matsumoto 7ice DNA Polymerase Beta Anti-cancer 1a25 Protein Kinase C Inhibitor Confirmed Induction of apoptosis in tumor. Martelli Nieves-Neira 1cdk CAMP-Dependent Protein Kinase Anti-cancer 3bct Beta-Catenin Anti-cancer 1dvi Calpain Inhibition of calpain activities. Implicated Induces apoptosis in leukemic cells. Eymin 1yfo Receptor Protein Tyrosine Phosphatase Causes elevation of PTPase in the cytosol and the nucleus which play a critical role in the induction of the differentiation of IW32 erythroleukemia cells. Implicated Anti-cancer Wang MC 1a35 Topoisomerase I Inhibitor Confirmed Anti-cancer Wang MC

  24. Putative and known therapuetic targets of Camptothecine identified from INVDOCK search of human and mammalian proteins PDB Protein Experimental Finding Target Status Theraputic Effect Ref 1ads Aldose Reductase Diabetes treatment 2gss Glutathione S-Transferase p1-1 Increases intracellular glutathione Implicated Enhance radical scavenging activities that may useful in cancer treatment Matsumoto 7ice DNA Polymerase Beta Anti-cancer 1a25 Protein Kinase C Inhibitor Confirmed Induction of apoptosis in tumor. Martelli Nieves-Neira 1cdk CAMP-Dependent Protein Kinase Anti-cancer 3bct Beta-Catenin Anti-cancer 1dvi Calpain Inhibition of calpain activities. Implicated Induces apoptosis in leukemic cells. Eymin 1yfo Receptor Protein Tyrosine Phosphatase Causes elevation of PTPase in the cytosol and the nucleus which play a critical role in the induction of the differentiation of IW32 erythroleukemia cells. Implicated Anti-cancer Wang MC 1a35 Topoisomerase I Inhibitor Confirmed Anti-cancer Wang MC

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