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Lecture 7 computer aided drug design
- 1. Lecture 7- Computer aided drug design BTT- 516– Drug Designing and Development
- 2. Introduction Role of CADD Impact of structural Bioinformatics on Drug Discovery Drug Designing A ppro a c h e s Steps involved in Drug designing D o c k ing Topics to be covered today
- 3. DRUG • A drug may be defined as “a chemical entity that when consumed/injected, results in the control or eradication of a particular disease/infection”. • Drug discovery is a pipeline process involved in the evolution of drugs and involves “genes to drugs” strategy. • Identifying the gene responsible for a particular disease process and finally evolving a drug to combat the disease-these three forms the main areas in this strategy.
- 4. Computer Aided Drug Design • Drug discovery process usually starts with an analysis of binding sites in target proteins or an identification of structural features common to active compounds. • The process ends with the generation of small molecule “leads” suitable for further chemical synthetic work. • It is a recent and emerging discipline that uses several bioinformatics tools and related fields like chem informatics and combinatorial chemistry. • CADD uses computational chemistry to discover, enhances or study of drugs and related biologicallyactive molecules.
- 5. Role of CADD • The target of computer assisted drug design (CADD) is not to find the ideal drug but to identify and optimize lead compounds and save some experiments • The parameters expected from a drug are • Safety • Efficiency • Stability • Solubility • Synthetic viability • Novelty
- 6. Hits Lead and Drugs • Hits are chemical compounds that produce biological activity through to represent therapeutic potential. • Biological screening is carried out to identify those compounds that possess the biological activity, better than the ‘hits’. such compounds identified are called ‘leads’. • Drugs are small molecules that bind, interact, and modulate the activity of specific biological receptors •The initial leads are unlikely to be the final drugs. complex evaluations are necessary and typically the initial hit is modified atom-by-atom to improve important as a characteristic of the molecule. •The choice of lead structure is very important for success in drug development.
- 8. Impact of structural Bioinformatics on Drug Discovery Speeds up key steps in DD process by combining aspects of bioinformatics, structural biology, and structure-based drug design
- 9. Identify disease Isolate protein GENOMICS, PROTEOMICS & BIOPHARM In silico & In Vitro ADME MODELS Potentially producing many more targets and “personalized” targets HIGH THROUGHPUT SCREENING Screening up to 100,000 compounds a day for activity against a target protein VIRTUAL SCREENING Using a computer to predict activity Combinatorial Chemistry Rapidly producing vast numbers of compounds Molecular Modeling Computer graphics & models help improve activity Tissue and computer models begin to replace animal testing Find drug Preclinical testing
- 10. Drug Designing Approaches There are four basic approaches for drug designing 1. Ligand based approach 2. Target based approaches 3. DE NOVOApproaches 4. SBDD
- 12. DE NOVO Approaches • DE NOVO design is the approach to build a customized ligand for a given receptor. • This approach involves the ligand optimization • Ligand optimization can be done by analyzing protein active site properties that could be probable area of contact by the ligand. • The analyzed active site properties are described to negative image of protein such as hydrogen bond, hydrogen bond acceptor and hydrophobic contact region.
- 13. Steps involved in Drug designing 1. Targetidentification 2. Target validation 3. Lead identification 4. Lead optimization 5. Docking 6. Pre Clinical Trials 7. Clinical trails
- 14. Ta r g etIdentification • A target is a molecule (namely a protein) which is present within an organism. • The approaches of identifying targets include expression, protein biochemistry, structure studies, study of biochemical pathways. • There are now several other methods to identify specific molecular targets like high throughput sequencing analysis, positional cloning, generation of cDNA libraries with ESTS and database mining by sequence homology. • It is important to determine whether the novel targets are actually relevant to the physiology of the disease.
- 15. Ta r g etVa lida tion As there are a pleothora of new potential therapeutic drug targets that are being discovered, selection and validation of novel molecular targets has become important. It needs to be confirmed that the targets identified will affect an appropriate biological response. Targeted gene disruption (TGD) is a term that refers to several different methods of target validation.
- 16. Lead Identification •Lead is a compound (usually a small organic molecule) that demonstrates a desired biological activity on a validated molecular target. • To be termed as a lead, the compound must exceed a specific potency threshold against the target. • The compounds used as potential leads can be from many sources. the most important sources of leads is libraries of molecules like peptide libraries, natural compounds
- 17. • Once a lead compound is established in the identification process, we need to optimize the desirable traits of the lead. • To be considered for further development , lead should be amenable for chemistry optimization. Lead Optimization
- 18. Docking • Docking refers to the ability to position a ligand in the active or a designated site of a protein and calculate the specific binding affinities. • Docking algorithms can be used to find ligands and binding conformations at a receptor site close to experimentally determined structures. • Docking algorithms are also used to identify multiple algorithms and also used to identify proteins to which a small molecule can bind. Some of the docking programs are GOLD (genetic optimization for ligand docking), AUTODOCK, LUDI, HEX etc.
- 20. Active Site Prediction Rolta et al., 2021
- 21. Mechanism of Drug Binding
- 23. Protein-Ligand Docking Rolta et al., 2021
- 24. Protein-Ligand Docking Rolta et al., 2021
- 25. Protein-Ligand Docking Rolta et al., 2021
- 26. Examples of drugs designed by structure- based methods • Human Renin Inhibitor Antihypertension • Collagenase and Stromelysin Inhibitor Anticancer andAntiarthritis • Purine Nucleotide Phosphorylase Inhibitor • Antidepressant • Thymidylate Synthase Iinhibitor Antiproliferation NATURE 384 SUPPL, 23-26 (1996)
- 27. Thank you Er. Rajan Rolta Faculty of Applied Sciences and Biotechnology Shoolini University, Village Bhajol, Solan (H.P) +91-7018792621 (Mob No.) rajanrolta@shooliniuniversity.com