Molecular modelling and dcoking.pptx
- 1. MOLECULAR MODELLING AND DOCKING CONTENTS: • MOLECULAR DOCKING AND DRUG RECEPTOR INTERACTION -Rigid docking -Flexible docking -Extra precision docking • AGENTS ACTING ON ENZYME - DHFR (Dihydro folate Reductase) - HMG-CoA reductase - HIV protease - Choline esterase (AchE & BchE)
- 2. • Molecular modelling is theoretical method and computational techniques used to mimic the behavior of molecules and molecular system. • Molecular modelling helps the scientist to visualize molecule, to discover new compounds for drug. • The common feature of molecular modelling technique is atomistic level description of the molecular system. DEFINITION: Molecular modelling is a combination of bio-informatical and biophysical techniques to represent and visualize the shapes of molecules in space, and to simulate the way they move and behave. • Visualize 3D structures and to simulate, predict and analyze the properties, the behavior of the molecules on a atomic level to data mining and to organize many compounds and their properties into database and to perform virtual drug screening via 3D database screening for novel drug compounds.
- 3. DEFINITION: Molecular docking is a method to identify the architecture of compounds generated by two or more distinct molecules computationally. The objective of docking studies is to anticipate the desired three-dimensional structures. • Predicting the protein-ligand complexes in which the ligand molecules interact with the binding site of receptor. • The ligand protein interaction are various type i.e vanderwaal, electrostatic, hydrogen bonding. • Successful docking methods search high dimensional space effectively and use a scoring function that correctly ranks candidate docking. • Molecular docking is one of the most frequently used methods in structure based drug design due to its ability to predict the binding confirmation of small molecule ligand to the appropriate target binding site. • Characterisation of the binding behavior plays an important role in rational design of drugs as well as to elucidate fundamental biochemical processes. MOLECULAR DOCKING
- 5. KEY STAGES IN DOCKING A) RECEPTOR SELECTION AND PREPARATION i) BUILDING RECEPTOR: The 3D structure of receptor is downloaded from PDB. This receptor must be biologically active and stable, II) IDENTIFICATION OF ACTIVE SITE: The receptor can have many site but interested one should be selected B) LIGAND SELECTION AND PREPARATION i) Ligand can be selected from PubChem, Chem-sketch, Chem-spider. ii) The ligand is docked onto the receptor and the interaction are checked. iii) The scoring function generates scores depending which the best fit ligand is selected.
- 6. DOCKING TOOLS Docking Software Software Year AutoDock 1990 DOCK 1988 FlexAID 2015 LeDOCK 2016 Glide 2004 https://en.wikipedia.org/wiki/List_of_ protein-ligand_docking_software Docking Algorithm Lamarckian Algorithm Genetic Algorithm Genetic Algorithm Monte Carlo Sampling Monte Carlo Sampling
- 7. TYPES OF DOCKING There are two distinct forms of docking. 1. Rigid docking 2. Flexible docking A) RIGID DOCKING Assuming the compounds are inflexible, we are seeking a rearrangement of one of the compounds in three dimensional space that results in the best match to the other compounds in parameters of a scoring system. The ligand’s conformation can be formed with or without receptor binding activity. B) FLEXIBLE DOCKING In conjunction with transformation, we evaluate molecular flexibility to identify confirmations for the receptor and ligand molecules as they exist in the complex.
- 8. 1.RIGID DOCKING/THE LOCK AND KEY THEORY 2. FLEXIBLE DOCKING/THE INDUCED-FIT THEORY In Rigid docking both the internal geometry of receptor and ligand is kept fixed and docking is performed. In Flexible docking an enumeration on the rotations of one of the molecules is performed. Every rotation the surface cell occupancy and energy is calculated later the most optimum pose is selected.
- 9. RIGID DOCKING • Historically first approach • Protein and ligand are fixed • Search for two orientation of two molecules with lowest energy • It is a protein docking • Both molecules usually considered rigid • Steric constraints are applied to limit search space and then examine energetics of possible binding conformations • Protein ligand docking • Flexible ligand rigid receptor • Search space much larger • Either reduce flexible ligand to rigid fragments connected by one or several hinges, or search the conformational space suing monte-carlo methods or molecular dynamics. FLEXIBLE DOCKING
- 10. SCORING FUNCTIONS • The evaluation and ranking of predicted ligand conformations is a crucial aspects of structure based virtual screening. • It makes various assumptions and simplification in the evaluation of modeled complexes. • They do not fully account for a number of physical phenomena that determines molecular recognition. • Following types of scoring functions are currently applied: -Force field based scoring -Empirical scoring -knowledge based scoring -shape and chemical complementary scoring APPLICATIONS • Generation of chemical structures • Generation of conformations • Docking (Molecular interactions) • Drug excipient interactions • Lead generation • Hit identification
- 11. DIHYDROFOLATE REDUCTASE (DHFR) - It is a reductase enzyme found in all dividing cells of eukaryotes and prokaryotes. - It catalyzes the reduction of 7,8 dihydrofolate through stereospecific hydride transfer to produce 5,6,7,8 Tetrahydrofolate product.
- 12. MECHANISM OF ACTION - Tetra hydrofolate (FH4) is produced from the vitamin Folate (B9) which is a one carbon carrier compound. -while one carbon units are attached to FH4 at N5 and N10 (bridge forming between N5 and N10) by donation of amino acids (majorly serine, histidine) they can be oxidized and reduced depending upon the requirement by biochemical reaction. -one of the major acceptor of this is deoxy-uridine monophosphate which accepts N5,N10-methylene from FH4 to yield deoxy thymidine monophosphate (dTMP), purine precursor. -this is essential for purine and thymidylate synthesis which are important for cell growth and cell proliferation.
- 13. • It is a cytosolic protein (186 amino acids) of 21.3kDa and uses NADPH as a cofactor. • DHFR sequence in humans is 30% similar to that of E.coli and 70% similar to other mammalians. • Standard source of this enzyme is mammalian and avian liver. • In human this enzyme is encoded by DHFR gene. It is found in the q11-q22 region of chromosome 5. DHFR STRUCTURE
- 14. LIST OF VARIOUS INHIBITORS ACTING ON DHFR ENZYMES 1. TRIMETHOPRIM: BLOCKS BACTERIAL ENZYMES 2. PYRIMETHAMINE: PROTOZOAL ENZYME 3. METHOTRAXATE: MAMMALIAN ENZYME 1. TRIMETHOPRIM:
- 15. 2.METHOTRAXATE -It is a DHFR reductase inhibitor used to treat autoimmune inflammatory disease such as rheumatoid arthritis.
- 16. 3.PYRIMETHAMINE - It directly acting inhibitor of plasmodial DHFRase - It gradually reduces the schizogony of malarial parasite in blood - It is slowly acting erythrocytic schizontocide.