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New drug discovery
- 2. Introduction
- 5. Docking as a target identification tool Docking: Computational search for energetically favorable binding poses of a ligand with a receptor. Find origins of ligand binding which drive molecular recognition. • Finding the correct pose, given a ligand and a receptor. • Finding the best ligand, given a database and a receptor.
- 9. 1. Transgenic Animals Transgenic animals are created by deliberately inserting a gene into the genome of an animal. Recombinant DNA methodology is used to construct the gene that is intended to express desirable qualities during the growth and development of the recipient animal. Transgenic animal models allow unprecedented control over manipulation and visualization of genes and gene products. Transgenic rats as model are used for: • Hypertension • Atherosclerosis • Alzheimer’s disease
- 10. 2. Antisense technology In Antisense technology, synthetically produced complementary molecules seek out and bind to messenger RNA (mRNA), blocking the final step of protein production. mRNA is the nucleic acid molecule that carries genetic information from the DNA to the other cellular machinery involved in the protein production. By binding to mRNA, the antisense drugs interrupt and inhibit the production of specific disease-related proteins.
- 11. 3. Chemical Genomics Chemical genomics or chemogenomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically, some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified.
- 13. The Hit Discovery Process Physiological Screening 01 High Throughput Screening 02
- 14. 1. Physiological Screening A tissue-based approach and looks for a response more aligned with the final desired in vivo effect as opposed to targeting one specific molecular component.
- 15. 2. High Throughput screening Standard method for drug discovery 1000’s of compounds possess potential of emerging as a new drug are tested using automated machines Tested for their ability to modify the properties of a selected biological target Remove inactive compounds at initial stage and accumulate active compounds. The main goal is to accelerate drug discovery process by screening large libraries
- 17. Lead Optimisation Strategies 1. Absorption Strategies 2. Distribution Strategies 3. Metabolism Strategies 4. Excretion Strategies 5. Insilico ADME Screening
- 18. 1. Absorption Strategies • Animal studies (rat) – Very low throughput • In situ intestinal models – Very low throughput, expensive • Intestinal epithelial barrier models a) MDCK cell line b) HT29 cell line c) Caco-2 cell line
- 22. 3. Metabolic Strategies Assessment of Metabolic Stability Metabolite Characterization
- 23. 4. Excretion Strategies In vivo excretion studies are not usually performed in lead optimization In vitro models to investigate renal excretion are very limited. The primary in vitro renal excretion model is the isolated perfused rat kidney
- 24. 5. Insilico ADME Strategies Availability of massive ADME and PCK data in the literature and within the pharmaceutical company databases has led to the initiation of datamining efforts in order to understand the SAR for ADME properties. a) Molecular Based Modeling b) Data Based Modeling
- 26. Prediction of Drug Safety 1. In vitro methods 2. In vivo methods 3. Ex vivo methods
- 27. 1. In vitro methods In vitro methods are complicated due to • Difficulties of maintaining cells in culture • Lack of understanding of the humoral and matrix requirements
- 28. 2. In vivo methods In vivo methods are focused on determining safe doses for PCK (phase I) studies by measuring tolerable and toxic doses
- 29. 3. Ex vivo methods Ex vivo methods analyze tissues, tissue extracts, or fluids from animals previously exposed to lead candidates and the comparison of these results to those derived from untreated animals.
- 30. Estimation of Starting Dose for Phase I
- 31. Estimation of Starting Dose for Phase I Determine NOAEL (mg/kg) in toxicity studies Convert each animal NOAEL to HED (based on body surface area) Select HED from most appropriate species Choose safety factor and divide HED by that factor Maximum Recommended Starting Dose (MRSD)
- 32. Phases of Clinical Trail
- 33. Phases of Clinical Trails Phase 4 Post Marketing Studies Phase 3 Therapeutic Confirmatory Phase 2 Therapeutic Exploration Phase 1 Human Pharmacology
- 34. Conclusion
- 35. Conclusion Whatever the strategy, it is ultimately the drug that speaks. A development program will typically have one or more “champions” and several stakeholders from numerous disciplines who may rationalize why the drug candidate should continue along the development path instead of intaking the difficult decision to terminate the program. The basic paradigm will continue to comprise intense planning, strategic decision making, extensive research, long term nonclinical safety, and clinical safety and efficacy studies, comprehensive data collection and statistical analyses, and relevant support programs.