1. Principles of drug discovery : by kavya lakshmi.v (Pharmacology) Under the guidance of : Dr T.Vedhavathi Mpharm ;PhDCmr collage of pharmacy

2. Principles of drug discovery

3. Drug discoveryDef: The process of drug discovery involves the identification of lead and its targets, synthesis, characterization, screening, and assays for therapeutic efficacy of lead. Once a compound has shown its value in in these tests, it will begin the process of drug development prior to clinical trails.The average time required to bring a drug to the market range from 12–15 years at an average cost of $600–800 million

4. Stages in drug discovery Drug discovery Formulation Preclinical studies Clinical trails Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has passed all regulatory requirements.

5. Process of drug discovery

6. Drug development Target :Naturally existing cellular or molecular structure involved in the disease pathology on which the drug acts Targets Types Target validation :Involves demonstrating that a molecular target is critically involved in a disease process & modulation of the target is likely to have a therapeutic effect

7. Screening & design Screening :Investigation of a great number of compounds for a particular problem or feature of them Random Screening Non-random Cross Random involves no intellectualization & assays are done with out structural regards Non-random also known as targeted or focused & more narrow approach. compounds having a vague resemblance to weakly active compounds uncovered in a random screened Whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening

8. Techniques in screening High through put screening :ideal technique which involves the molecule finding in such a way that hits only the chosen target even not the related It is often done for a molecule which already has some of the desired properties Virtual high through put screening : where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used. This is hit-lead phase is followed

9. Approches Nature of sources Chemical sources Rational approches Molecular modelling Combnitorial chemistry Biotechnology Bioinformatics Preclinical studies Clinicaltrails

11. Many cardiotonics are plant derived

12. Microbes are the main source of antimicrobial drugs

13. Streptomyces species have been a source of antibiotics.

14. Marine environments are potential sources for new bioactive agents.

17. Split Synthesis: Peptide Libraries

18. Encoding Combinatorial Libraries

19. Nonpeptide LibrariesThe main differences among the various combinatorial approaches are the solid support used, the methods for assembling the building blocks, the state (immobilized or in solution) and numbers (a fraction of the total library or individual entities)

20. Rational approches Hit -Lead:

21. Molecular modeling Structure Modifications to Increase Potency and the Therapeutic Index 1 Homologation 2 Chain Branching 3 Ring-Chain Transformations 4 Bioisosterism 5 SAR by NMR/SAR by MS 6 CADD

22. Homologation : prolongation of saturated carbon chain with groups that differ by a constant unit to increase pharmacological effect & lipophilicity Chain branching :this involves the side branching of alkyl groups instead of long straight chain alkyl groups Ring chain transformation :effective pharmacokinetic properties are obtained by transformation of alkyl substituent's into cyclic analogs Bioisosterism :Bioisosterism is an important lead modification approach that has been shown to be useful to attenuate toxicity or to modify the activity of a lead

23. SAR/NMR :This approach, termed SAR by NMR, was initially used to discover compounds with nanomolar affinitiess by tethering two molecules with micro molar affinities (low potency). CADD :Computer-aided design (CAD), also known as computer-aided design and drafting (CADD) , is the use of computer technology for the process of design and design-documentation. Computer Aided Drafting describes the process of drafting with a computer

24. Technological Approach ssss

25. Preclinical studies Acute Studies :The goal is to determine toxic dose levels and observe clinical indications of toxicity. Data from acute toxic studies helps determine doses for repeated dose studies in animals and Phase I studies in humans. Repeated Dose Studies :These are repeated dose studies may be referred to as sub acute, sub chronic, or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required. Genetic Toxicity Studies :These studies assess the likelihood that the drug compound is mutagenic or carcinogenic.

26. Reproductive Toxicity Studies : Segment I reproductive toxic studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development Carcinogenicity Studies :Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions Toxicokinetic Studies :These are typically similar in design to PK/ADME studies except that they use much higher dose levels. They examine the effects of toxic doses of the drug and help estimate the clinical margin of safety

27. Preclinical studies & Clinical trails

28. Clinical trails

29. Clinical trails Phase I:No blinding screening,open label & done in single centre

30. Phase II :Therapeutic exploration & dose ranging May be blind or open label (4centre’s or more)

31. Phase III :Therapeutic confirmation or comparison Done in multicentre

32. Post marketing surveillance : study of uncommon or idiosyncratic ADR dose who occur only after long term use & unsuspected drug interactions Patients treated in the normal course form the study population It includes special cases like pediatrics ,pregnant women renal & hepatic diseased persons who are excluded in the previous stages of clinical trails Modification drug delivery systems ,route of administration, fixed drug doses ,drug combinations etc are explored here

33. Novel approaches Micro array techniques Peptidomimetics Pharmacogenomics Proteomics Chemi-informatics

34. Conclusion

35. Queries