Structure based drug designing
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This document discusses structure based drug design. It describes how drug design uses knowledge of biological targets to find new medications. Structure based drug design uses information about the 3D structure of protein targets to design ligands that bind to them. The main methods described are ligand-based drug design through database searching, and receptor-based drug design which builds ligands for a receptor. Molecular docking is also discussed as a key technique to predict how ligands bind to protein targets and identify potential drug candidates.
Structure based drug designing
- 1. STRUCTURE BASED DRUG DESI GNING GROUP NO.6
- 2. What is Drug? Drug is an organic small molecule design to bind, interact, and modulate the activity of specific biological receptors.
- 3. Drug Designing Drug design, often referred to as ration al drugdesign or simply rational design, is the inventive process of finding new m edications based on the knowledge of a b iological target.
- 4. Aims of Drug Design Relation of chemical structure to biological activity. Conduction of structure activity analysis Prediction of given molecule bind to target .
- 5. STRUCTURE-BASED DRUG DESIGN. DEFINITION: "It is the design and modification of a chemical str ucture with the aim of identifying a compound suit able for clinical testing, basically a drug candidat e in medicinal chemistry studies”. DESCRIPTION: It is one of the first techniques to be used in drug design. It has helped in the discovery process of new drugs.
- 6. METHODS: 1. Ligand based Drug Design Or Database Se arching: The first category is about “finding” ligands f or a given receptor, which is usually referred as database searching. 2. Receptor based Drug Design: Second category is about “building” ligands, which is usually referred as receptor- based drug design.
- 7. STRUCTURE BASE DRUG DE SIGN PROCESS
- 8. DOCKING • In the field of molecular modelin g docking is a method which pre dicts the preferred orientation o f one molecule to a second when bound to each other to form a st able complex. • Molecular docking is one of the most frequently used methods in structure based -designing due to its ability to predict the bindi ng-conformation of small molecu le ligands to the appropriate tar get binding site.
- 9. DOCKING METHADOLOGIES: 1.Rigid ligand and rigid receptor docking When the ligand and receptor are both treated as ri gid bodies, the search space is very limited, considerin g only three translational and three rotational degree s of freedom 2.Flexible ligand and rigid receptor docking In that case both the ligand and receptor change th eir conformations to form a minimum energy perfect-f it complex. Thus the common approach, also a trade-of f between accuracy and computational time, is treatin g the ligand as flexible while the receptor is kept rigid during docking.
- 10. 3. Utilizing rotamer libraries Rotamer libraries include a set of side-chain conformations which are usually determined from statistical analysis of structural experi mental data. 4. AutoDock Adopt a simultaneous sample method to de al with side chain flexibility. Several side ch ains of the receptor can be selected by users and simultaneously sampled with a ligand us ing the same methods.
- 11. Theory of docking Essentially, the aim of molecular docking is to give a pr ediction of the ligand-receptor complex structure using computation methods. Docking can be achieved throug h two interrelated steps: first by sampling conformatio ns of the ligand in the active site of the protein; then ra nking these conformations via a scoring function.
- 12. SCORING Each solution should be tested during structural based drug designing to decide which is the most promising, this is called as scoring.
- 13. SCORING TYPES • FORCE FIELD SCORING: Force fields are mainly used to compute the inte raction energy between the protein and the ligan d. • EMPERICAL SCORING: It is based on the descriptors that describe the b inding event. • KNOWLEDGE BASED SCORING: It is based on the statistical analysis of interacti ng atom pairs from protein–ligand complexes.
- 14. APPLICATION OF DOCKI NG Hit identification lead optimization Bioremediation Used to predict pollutants that can be degraded by enzymes docking with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest Used to predict in where and in which relative orientation a ligand binds to a protein.
- 15. USES OF DOCKING Drug target Protein ligand interactions Better understand the machinery of life Enzyme-inhibitor class Antibody-antigen class Protein therapies Engineered protein enzymes
- 16. DE NOVO DRUG DESIGN De novo means starting from the scratch or fresh, or from very beginning. PRINCIPLE: • Assemble possible compound and evaluate their quality. • Searching sample space from novel structure wi th drug like properties
- 18. SUCCESSFUL CONTRIBUTIONS OF SBDD Example of application of SBDD was the design of HIV-I protease inhibitor. It is made up of 2 halves. It looks like a butterfly. Normally in symmetric molecules, both halves have active sites to carry enzyme job but in HIV-I protease, only one activ e site is present in the center of both hal ves. By the help of SBDD, his active site is pl ugged by a small molecule so that the en zyme is shut down and stop the virus sp read in the body.
- 19. EXAMPLES OF SBDD Ritonavir is one of a class of anti-HIV drugs, whic h is a protease inhibitor. Indinavir is another example of very potent pepti domimetic compound discovered using the eleme nts of 3D structure and Structure Activity Relati onship.