1. Drug Design: Discovery, Development and Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University BELGAUM – 590010 E-mail: [email_address] Cell No: 0091 9448716277
9. Computer-assisted Drug Design (CADD) In CoMFA map the colored fields describe how molecular structure can be modified to increase biological activity (CoMFA-Comparative molecular field analysis)
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11. Computer-assisted Drug Design (CADD) 3D models of membrane receptors can be refined and validated in a realistic lipid-water-salt environment using molecular dynamics simulations
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13. Computer-assisted Drug Design (CADD) New potent inhibitor for the Human Sirutuin Type 2 enzyme was found using a virtual screening technique
18. Dermatology Inflammatory/ Immune-related Oncology/ Cancer Respiratory Cardiovascular/ Blood Disorder Musculoskeletal Infectious Disease Microbial/Viral Neurological/ Pyschotherapeutic Ophthalmic Metabolic Gastrointestinal Important DRUG Targets Focused Areas of Research
19. Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development
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21. Drug Discovery Pipeline Validated Targets Hot Leads Drug Candidates ADME PK Human Trials H-UHTS Primary Screening Secondary Screening Lead Identification Lead Optimization Pre-clinical Clinical Discovery Development M-HTS Lab & Animal Tests L-MTS Clinical Validation Genome Sequencing SNP Discovery Genotyping Gene Expession Profiling Exploratory Research Genomics Proteomics Drug Discovery Fractionate Protein Mass Spec Combichem Synthesis Natural Compounds Compound Library Pathway Mapping Protein Structure Functional Genomics Protein- protein Interactions Protein Localization Expression Profiling Peptide Mass Fingerprinting Production Diagnostics
22. Drug Discovery Process Assay Development Discovery Center w/primary & secondary screening & Pre-ADME In vitro & in-vivo ADMET Compound library generation Combichem Clinical Trials & Clinical monitoring Functional and ADMET screening assays becoming more important earlier in the screening process. Exploratory Drug Discovery Drug Development New Drug Target Identification Target Qualification Validation Lead Identification Lead Optimization Preclinical Development Clinical Development NDA
23. “ Real drug “pipeline ” Drug Targets A – Absorption Solubility Stability Dissolution Drug Transport D - Distribution Plasma Protein Binding assays (PPB) “ Permeability” Drug Drug
24. Cell Membrane Transport Mechanisms Transcellular Paracellular Active Transport Active Efflux
34. Stomach pH2 Intestine pH3-8 PV Blood Kidneys Tissues Cell Target Stability Acidic buffer Stability Acidic enzymatic buffer Solubility pKa Stability CYP3A metabolic stability Permeability Passive P-gp efflux Transportes Log D Liver Phase I and II Metabolic stability Metabolite ID Protein binding RBC uptake Stability Enzymatic Plasma stability Renal Extraction Log D Permeability Passive Transporters Log D Cell Exposure Barriers of Drug Reaching Target
35. Candidate Selection: Building “Developability” in Preclinical Profiling Lead (active molecule) Metabolism Selectivity Potency LO (optimized molecule) Potency Selectivity Metabolism Physical properties Best leads Physical / chemical properties Biopharmaceutics
37. Solubility, Permeability, Chemical and Metabolic Stability Affects Oral Bioavailability Solid Drug Drug in Solution Absorbed Drug Dissolution Membrane Transfer Solubility Permeability Systemic Circulation Metabolism Liver Extraction Portal Vein
38. Physico-chemical profile of NCEs Permeability pKa Stability PPB Log D Polymorphism Lipophilicity Solubility Integrity Profile
39. Successful Drug = Activity + Property Optimization Activity Pharmacology Property Pharmaceutical Profiling In vitro Solubility Permeability BBB & Pgp Log P & pKa Metabolism P450 Inhibition Stability Pharmacokinetics In vivo Enzyme Receptor Cell-based assay In vitro Animal Model In vivo Redesign