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

2. Drug Design

6. Rational Drug Design Refining the understanding of pathogenesis

7. Rational Drug Design Investigating complex systems increases knowledge return

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)

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

13. Computer-assisted Drug Design (CADD) New potent inhibitor for the Human Sirutuin Type 2 enzyme was found using a virtual screening technique

16. Drug Discovery

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

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

26. Ion channels are membrane spanning proteins

27. Opening and closing of channels requires conformational change

28. Extracellular Intracellular Flux of ions through the channels is passive

29. Drug Development

31. Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development

32. Drug Development Process

33. Reasons for Attrition in Drug Development

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

36. Stability in Physiological Conditions Duodenum Stomach Ascending colon Descending colon Jejunum Ileum Small intestine Transverse colon Rectum pH = 1 - 3.5 pH = 5 - 7 pH = 8 Blood = 7.4

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

40. Drug Development Process

41. Drug Delivery

46. Context – Drug Delivery

47. Context – Drug Delivery

48. Drug Delivery - Markets

49. Drug Delivery Systems Nano Technology DDS Buccal DDS Rectal DDS Vaginal DDS Pulmonary DDS Nasal DDS Topical DDS Parentral DDS Oral DDS Delivery Systems

50. Thanx for your …..