1. 19 March 2009KLE College of Pharmacy, Belgaum 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: bknanjwade@yahoo.co.inbknanjwade@yahoo.co.in Cell No: 0091 9448716277

2. 19 March 2009KLE College of Pharmacy, Belgaum 2 Drug Design

3. 19 March 2009KLE College of Pharmacy, Belgaum 3 Drug Design  Drug design is the approach of finding drugs by design, based on their biological targets. Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen.drugsbiological targetsmoleculemetabolic pathwaypathologyinfectivitymicrobialpathogen  Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state.  In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are designedmedicinebiotechnologypharmacologydrugs

4. 19 March 2009KLE College of Pharmacy, Belgaum 4 Drug Design 1. Rational Drug Design 2. Computer-assisted Drug Design (CADD) 3. Neural network in Drug Design

5. 19 March 2009KLE College of Pharmacy, Belgaum 5 Rational Drug Design The industry now has the research tools to pursue rational Drug Design successfully, but a new hurdle is being raised:finding a way to generate data and manage our knowledge of disease that maximizes the value of that knowledge 1. Molecular properties 2. Receptor-Based modeling 3. Numerical methods

6. 19 March 2009KLE College of Pharmacy, Belgaum 6 Rational Drug Design Refining the understanding of pathogenesis

7. 19 March 2009KLE College of Pharmacy, Belgaum 7 Rational Drug Design Investigating complex systems increases knowledge return

8. 19 March 2009KLE College of Pharmacy, Belgaum 8 Computer-assisted Drug Design (CADD)  Drug design is a three-dimensional puzzle where small drug molecules, ligands, are adjusted to the binding site of a protein.  The factors which affect the protein-ligand interaction can be characterized by using molecular docking and different quantitative structure-activity relationships (QSAR) methods

9. 19 March 2009KLE College of Pharmacy, Belgaum 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)

10. 19 March 2009KLE College of Pharmacy, Belgaum 10 Computer-assisted Drug Design (CADD)  The most commonly used tool to model biological system is molecular dynamics  The model of a receptor refined with molecular dynamics simulations

11. 19 March 2009KLE College of Pharmacy, Belgaum 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

12. 19 March 2009KLE College of Pharmacy, Belgaum 12 Computer-assisted Drug Design (CADD )  Virtual screening is a computational technique to find novel drug candidates.  Data from virtual screening can be used to develop predictive models in order to optimize ADMET properties of the candidate molecules.  The ultimate goal of this procedure is to find investing lead molecules that are worth for further drug research and synthesis.

13. 19 March 2009KLE College of Pharmacy, Belgaum 13 Computer-assisted Drug Design (CADD) New potent inhibitor for the Human Sirutuin Type 2 enzyme was found using a virtual screening technique

14. 19 March 2009KLE College of Pharmacy, Belgaum 14 Neural network in Drug Design  This is the most latest technique being applied to discover new drugs. It works on the same principles as the neural networks found in the human brain.  This technique makes use of Computer Artificial Intelligence, whereby a computer learns by itself, how to approach a target drug molecule and improves its iterations by itself.  This technique can be applied to solve complex drug calculations. Desktop computers as well as Super-Computers both are employed for Neural Networks Drug research.

15. 19 March 2009KLE College of Pharmacy, Belgaum 15 Applications 1. Find interesting lead molecules quickly 2. Predicting properties and activities of untested molecules 3. Propose compounds for synthesis 4. Validate models of receptor binding sites 5. Optimize pharmacokinetic properties of compound

16. 19 March 2009KLE College of Pharmacy, Belgaum 16 Drug Discovery

17. 19 March 2009KLE College of Pharmacy, Belgaum 17 Drug Discovery In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discoveredmedicinebiotechnologypharmacologydrugs The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy.

18. 19 March 2009KLE College of Pharmacy, Belgaum 18 Dermatology Inflammatory/ Immune-related Oncology/ Cancer Respiratory Cardiovascular/ Blood Disorder Musculoskeleta l Infectious Disease Microbial/Viral Neurological/ Pyschotherapeutic Ophthalmic Metabolic Gastrointestinal Important DRUG Targets Focused Areas of Research

19. 19 March 2009KLE College of Pharmacy, Belgaum 19 Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development

20. 19 March 2009KLE College of Pharmacy, Belgaum 20 1. What is an ideal drug? (Given by mouth and has a beneficial effect {safe & efficacious} in only ~ 50% !) 2. What is a promising drug candidate? (Most site specific with best combination of target affinity, highest bioavailability and lowest toxicity) 3. How is a ‘lead’ drug candidate screened for ideal characteristics? (Study of the in vitro ADME/Tox- drug transport, absorption, metabolism, etc) [Toxicity & pharmacokinetics: In vivo ] Drug Discovery Process

21. 19 March 2009KLE College of Pharmacy, Belgaum 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-clinicalClinical 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 FunctionalGenomics Protein- protein Interactions Protein Localization Expression Profiling Peptide Mass Fingerprinting Production Diagnostics

22. 19 March 2009KLE College of Pharmacy, Belgaum 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 ExploratoryDrug DiscoveryDrug Development New Drug Target Identification Target Qualification Validation Lead Identification Lead Optimization Preclinical Development Clinical Development NDA Functional and ADMET screening assays becoming more important earlier in the screening process.

23. 19 March 2009KLE College of Pharmacy, Belgaum 23 “Real drug “pipeline” Drug Targets A – Absorption Solubility Stability Dissolution Drug Transport D- Distribution Plasma Protein Binding assays (PPB) “ Permeability”

24. 19 March 2009KLE College of Pharmacy, Belgaum 24 Cell Membrane Transport Mechanisms Transcellular Paracellular Active Transport Active Efflux

25. 19 March 2009KLE College of Pharmacy, Belgaum 25 1.Membranes are two-dimensional solutions of oriented lipids and globular proteins that are mobile in the plane of the membrane – fluid-mosaic model 2.Membrane transport is mediated by specific integral membrane proteins – ion channels, porins, transporters (passive), pumps (active) 3.Integral membrane proteins have common structural features – predominantly transmembrane  helices Membrane structure & transport

26. 19 March 2009KLE College of Pharmacy, Belgaum 26 Ion channels are membrane spanning proteins

27. 19 March 2009KLE College of Pharmacy, Belgaum 27 Opening and closing of channels requires conformational change

28. 19 March 2009KLE College of Pharmacy, Belgaum 28 Extracellular Intracellular Flux of ions through the channels is passive

29. 19 March 2009KLE College of Pharmacy, Belgaum 29 Drug Development

30. 19 March 2009KLE College of Pharmacy, Belgaum 30 Drug Development  Drug development or preclinical development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials, although a broader definition would encompass the entire process of drug discovery and clinical testing of novel drug candidates. clinical trials

31. 19 March 2009KLE College of Pharmacy, Belgaum 31 Drug Discovery Pathway Efficacy ADME Toxicology Safety Preformulations Stability Studies Leads Selection of candidate drug Preclinical Studies Primary Screening [Hits] Discovery & Development

32. 19 March 2009KLE College of Pharmacy, Belgaum 32 Drug Development Process

33. 19 March 2009KLE College of Pharmacy, Belgaum 33 Reasons for Attrition in Drug Development

34. 19 March 2009KLE College of Pharmacy, Belgaum 34 Stomach pH2 Intestine pH3-8 PV BloodKidneysTissues 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. 19 March 2009KLE College of Pharmacy, Belgaum 35 Candidate Selection: Building “Developability” in Preclinical Profiling Lead (active molecule) Metabolism Selectivity Potency LO (optimized molecule) Physical properties Potency Selectivity Metabolism Best leads Physical / chemical properties Biopharmaceutics

36. 19 March 2009KLE College of Pharmacy, Belgaum 36 Stability in Physiological Conditions

37. 19 March 2009KLE College of Pharmacy, Belgaum 37 Solubility, Permeability, Chemical and Metabolic Stability Affects Oral Bioavailability Solid Drug Drug in Solution Absorbed Drug Dissolution Membrane Transfer SolubilityPermeability Systemic Circulation Metabolism Liver Extraction Portal Vein

38. 19 March 2009KLE College of Pharmacy, Belgaum 38 Physico-chemical profile of NCEs Profile IntegritySolubilityLipophilicityPolymorphismLog DPPBStabilitypKaPermeability

39. 19 March 2009KLE College of Pharmacy, Belgaum 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. 19 March 2009KLE College of Pharmacy, Belgaum 40 Drug Development Process

41. 19 March 2009KLE College of Pharmacy, Belgaum 41 Drug Delivery

42. 19 March 2009KLE College of Pharmacy, Belgaum 42 Drug Delivery  Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animalspharmaceuticaltherapeutic effecthumans animals  Drug Delivery technologies are patent protected formulation technologies that modifies drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy & safety and patient convenience & compliance

43. 19 March 2009KLE College of Pharmacy, Belgaum 43 Drug Delivery  Most common methods of delivery include the preferred non-invasive peroral (through the mouth), topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular and rectal) and inhalation routestopicalnasal buccalsublingualvaginalocularrectal inhalation

44. 19 March 2009KLE College of Pharmacy, Belgaum 44 Drug Delivery  Many medications such as peptide and protein, antibody, vaccine and gene based drugs, in general may not be delivered using these routes because they might be susceptible to enzymatic degradation or can not be absorbed into the systemic circulation efficiently due to molecular size and charge issues to be therapeutically effectivepeptideprotein antibodyvaccinegene  protein and peptide drugs have to be delivered by injection. proteinpeptide injection

45. 19 March 2009KLE College of Pharmacy, Belgaum 45 Drug Delivery  Current efforts in the area of drug delivery include the development of targeted delivery in which the drug is only active in the target area of the body (for example, in cancerous tissues) and in which the drug is released over a period of time in a controlled manner from a formulatetargeted deliverycancerous

46. 19 March 2009KLE College of Pharmacy, Belgaum 46 Context – Drug Delivery

47. 19 March 2009KLE College of Pharmacy, Belgaum 47 Context – Drug Delivery

48. 19 March 2009KLE College of Pharmacy, Belgaum 48 Drug Delivery - Markets

49. 19 March 2009KLE College of Pharmacy, Belgaum 49 Drug Delivery Systems Delivery Systems Oral DDS Parentral DDS Topical DDS Nasal DDS Pulmonary DDS Vaginal DDS Rectal DDS Buccal DDS Nano Technology DDS

50. 19 March 2009KLE College of Pharmacy, Belgaum 50