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DRUG DISCOVERY AND DEVELOPMENT

DRUG DISCOVERY AND DEVELOPMENT. M. Hanafi Puslit Kimia LIPI Kawasan PUSPIPTEK, Serpong. Research Phases in Drug Development. Target Identification And Validation. Idea. Search of Lead Structure. Lead Structure. Candidate for Development Product. Optimization of Lead Structure.

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DRUG DISCOVERY AND DEVELOPMENT

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  1. DRUG DISCOVERY AND DEVELOPMENT M. Hanafi Puslit Kimia LIPI Kawasan PUSPIPTEK, Serpong

  2. Research Phases in Drug Development Target Identification And Validation Idea Search of Lead Structure Lead Structure Candidate for Development Product Optimization of Lead Structure Preclinical Development Development Product

  3. DEVELOPMENT of NOVEL DRUGSfrom NATURAL PRODUCT Screening of Natural Compounds for Biological Activity : Soil, plants, fungi, etc 2. Isolation and Purification of Active Principle 3. Determination of Structure :NMR, IR, MS 4. Structure-Activity relationships(SAR) : Identification of Pharmacophore 5. Synthesis of Analogues : Increase activity, reduce side effects 6. Receptor Theories : binding site information 7. Design and Synthesis of Novel Drug Structure

  4. Lead compounds from Natural Products Vincristine (R = -CHO) – Vinblastine (R = -CH3) Vinca rosea (Catharanthus roseus) (Apocynaceae) Camptothecin Camptotheca acuminata Topotecan

  5. Discovery from Natural Products Lovastatin Aspergillus tereus Anticholesterol - Streptomycesp sp. 517-02 Cytotoxic to P338, KB Sulochrin - Antidiabetes Aspergillus terreus Calanone Callophyllum tesmanii Phenazine carbioxylate Pseudomonas pycocyaneae

  6. Lead Compounds Curcumin Piperine Gingerol

  7. Rational drug design • X-ray crystallography has developed so that the determination of the 3-D crystal structures of proteins and receptors is coming easier. • The Protein Data Bank (see http://pdb.ccdc.cam.ac.uk/pdb/) has data for hundreds of published structures which are all freely available • Coupled with advances in computing power and molecular modelling the so-called rational or structure-based drug design.

  8. Diagram 1. Natural Product Drug Development from new information to new therapy (Guo et al., 2006)

  9. Influencing Bio-molecular Processes Target = enzyme, receptor, nucleic acid, … Ligand = substrate, hormone, other messenger, ...

  10. Protein BcL-xL -

  11. Visualisasienzimα-Glukosidase Binding site prediction Positon of ligand in enzym target

  12. Enzym HMG-CoA Reductase

  13. Virtual Screening by in Silico Docking

  14. New Technologies and should Enable Parallel Process and Faster Time to Market at Lower Cost

  15. Drugs Fail Because of two Major Reason 39 % fail due to deficiencies in Absorption, Distribution, Metabolism & Elimination (ADME) 30% fail due to lack of efficacy 11% fail due to animal toxicity 10% fail due to adverse effects in man 5% fail due to commercial reason 5% miscellaneous

  16. Design of DHODH Inhibitors H-bonding, electrostatic and hydrophobic interactions can be identified and, hopefully, optimised by “in silico” design. hydrogen bonding hydrophobic π-stacking interaction

  17. Properties of orally Available Drug-like Compounds The Lipinski : Rule of five criteria Molecular weight 500 Da Log P ≤ 5 Hydrogen bond donors (OH and NH) ≤5 Hydrogen bond acceptors (lone-pairs of hetero-atoms, like O and N) Number of heavy atoms 10–70

  18. Curcumin PGV-0 PGV-1 HGV-1 HGV-0

  19. Cytotoxic effect of curcumin, PGV-0 and PGV-1 on some cell’s types (IC50 , M) Log P 2.56 3.19 2.94 * Concentrations to induce cell apoptosis as indicated by PARP cleavage

  20. Direct and structural analogues For “direct analogues”, a new lead must normally promise improvements in properties over an existing drug to be pursued. They are sometimes known as “me-too compounds”. For example ACE inhibitors: Enalapril Captopril Log P 0.24 Log P 3.09

  21. Success inspires competition Since the discovery of captopril many new ACE inhibitors have been discovered. The active site model of ACE was significantly improved, and the development of enalaprilat (enalapril) showed that carboxylates could be used as the zincbinding motif if the structure benefited from additional hydrophobic binding. IC50 4.08 1 IC50 75 18.33 Log P -0.92 Log P -0.1 Enalapril Log P 3.09 Log P -0.52

  22. DEVELOPMENT OF LOVASTATIN FoR ANTICHOLESTEROL

  23. Find and Optimized a Lead Compound: Lovastatin »Minimise energy of structure : Chem3D, Gaussian, Mopac, » QSAR (hub. Struktur Aktivits) : HyperChemPro » Direct Ligand Design (HMG-CoA rductase): Arguslab 4.0 » Synthesis » Bioaactivity Test

  24. METHODOLOGY Sintesis QSAR Parameter Identification Activity evaluation In vivo Active Anticholesterol compound Drug Design Hyperchem &Docking Evaluation Results Total cholesterol(mg/dl) Evaluation Results: HDL (mg/dl)

  25. HIPOTESIS “Perubahan Polaritas/Sterik “… makin mudah menembus dinding usus halus” = makin tinggi aktivitasnya

  26. DESAIN 2:Mengisi pusat aktif enzim [docking] Lovastatin fit terhadap enzim melalui 4 buah interaksi: Tabernero et al. J. Biol. Chem., 2003

  27. SIMVASTATIN & LOVASTATIN DERIVATIVES AND LOG P Log P 5.68 Log P 5.73 Log P 3.77 Log P 4.8 Log P 4.6

  28. HyperChem 7.0 ArgusLab 4.0 Interaction Dehydrolovastatin (grey) and the active site of HMG-CoA reductase (dark) INTERACTION ENERGY WITH HMG CoA REDUCTASE ANDLOG P

  29. Synthesis Dehydrolovastatin 88,3 % (EtOH) Lovastatin Heksan:EtOAC (4:1)

  30. Evaluation Results of Antihiperlipidemic Activity on Rat for Lipistatin and Simvastatin

  31. Development of UK-3A analog potential for Breast cancer treatment Structure AnalogDesign UK3A in silico Virtual Interaction (molecular docking) ArgusLabprogram Lipinski Rule Hyperchem Program MW < 500 g/mol; log P < +5

  32. Sel Normal vsSelKanker SelPayudara Normal • Protein-protein anti-apoptosis (a.l. Bcl-xL) diinhibisioleh protein-protein pro-apoptosis yang samabanyaknya SelKankerPayudara • Protein-protein anti-apoptosis (a.l. Bcl-xL) berlebih, sehinggaada yang tidakterinhibisi Akibat: Selpayudararusaktidakalami apoptosis; terustumbuhdanmembelahtidakterkendali (kanker) Simsteinet al, 2003.

  33. OBAT OBAT InhibisiBcl-xLdenganObat Bila kelebihan Bcl-xL diinhibisi, sel rusak akan alami apoptosis secara spesifik >> tidak jadi kanker Ricci, et al, 2006. Ghobrial, et al, 2005. Ferreira, et al, 2002.

  34. Optimum Conformation(Emin)- Chem3D Ultra 10 Chem3D Konformasi PDBGE Konformasi PDOGE

  35. HyperChem Pro (QSAR Parameter) & ArgusLab 4.0 (Ebinding) HyperChem Pro 7.0 ArgusLab 4.0 47 Interaction of Protein BcL-xL & Analog UK-3

  36. PSMOE PSMOE DEVELOPMENT OF ANALOG UK-3A POTENTIAL FOR BREAST CANCER TREATMENT BcL-xL Protein UK-3A Ring opening (Analog UK-3A) Analog UK-3A : PSMOE

  37. QSAR Parameter & Cytotoxic Test Results HClg/MeOH Log P -1.18 Ebinding = -7.1 kcal/mol IC50 = >100 mg/ml Log P 1.61 Ebinding = -11.65 kcal/mol P388 : IC50 = 38 mg/ml Log P 1.30, Ebinding = -10.24 kcal/mol KB :IC50 = 0.23 mg/ml YMB-1:IC50 = 0.015 mg/ml Log P 1.67 Ebinding = -10.39 kcal/mol

  38. Cytotoxic Test Results to P388, KB and YMB-1 Ebinding=-9.66 kcal/mol), Log P 1.5 IC50 34 mg/ml (P388) IC50 2.28 mg/ml (KB) IC50 1.83 mg/ml (YMB-1) Ebinding=-10.29 kcal/mol); Log P 1.62 IC50 38 mg/ml (P388) IC50 1.92 mg/ml (KB) IC50 5.46 mg/ml (YMB-1)

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