Structure based and ligand based drug designing
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This document discusses structure-based and ligand-based drug design approaches. Structure-based design uses the 3D structure of biological targets to dock potential drug molecules. Ligand-based design analyzes similar molecules that bind to the target to derive pharmacophore models or quantitative structure-activity relationships (QSAR) to predict new candidates. Specific structure-based methods covered include docking tools like AutoDock and CDOCKER, and accounting for protein and complex flexibility. Ligand-based methods discussed are QSAR techniques like Comparative Molecular Field Analysis (CoMSIA) and Field Analysis (CoMFA). In conclusion, computational approaches like these are valuable for drug discovery by facilitating the identification and testing of new ligand
Structure based and ligand based drug designing
- 1. STRUCTURE BASED AND LIGAND BASED DRUG DESIGNING VYSAKH MOHAN M DRUG DESIGNING
- 2. INTRODUCTION CADD STRUCTURE BASED DRUG DESIGNING LIGAND BASED DRUG DESIGNING
- 4. STRUCTURE BASED AND LIGAND BASED DRUG DESIGNING STRUCTURE BASED Don’t know ligands Know receptor structures LIGAND BASED Don’t know receptors Know ligands
- 7. STRUCTURE BASED DRUG DESIGNING Three dimensional structure of the biological target Obtained through x-ray crystallography or NMT spectroscopy If experimental structure is not available, create a homology model of the target, based on the experimental structure of a related protein Various automated computational procedures may be used
- 8. STRUCTURE BASED DRUG DESIGNING Protein structure determination Docking Binding free energy Flexibility of protein-ligand complex De novo evolution
- 9. PROTEIN STUCTURE DETERMINATION HOMOLOGY MODELING Fast method to obtain protein structures To ensure the rationality of modelled structures, checks on stereochemistry, energy profile, residue environments, and structure similarity are needed
- 10. PROTEIN STUCTURE DETERMINATION FOLDING RECOGNITION Threading Calculates the probabilities of 3D structures could form by given protein sequences Both environment of residues interactions and protein surface area are considered in the threading protocol Structure with highest probability is recommended to construct the protein model
- 11. PROTEIN STUCTURE DETERMINATION Ab initio PROTEIN MODELING Based on physical principles, residue interaction center and lattice representation of a protein to build the target Used when other protocols fail to predict and unknown protein structure Identity and accuracy given by this modelling is lower than others
- 12. PROTEIN STUCTURE DETERMINATION HOT SPOT PREDICTION One big issue in SBDD is to determine ligand active site Determined using X-ray crystallography But not possible for proteins that cannot be crystallised Several binding site determination methods have been invented
- 13. DOCKING A method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex
- 15. DOCKING TOOLS AUTODOCK Software AutoDock, developed by Olsen’s Laboratory A program for docking small flexible ligands into a rigid 3D structure
- 17. DOCKING TOOLS CDOCKER This protocol is a docking algorithm and retain all the advantages of full ligand flexibility Uses a sphere to define an active site, so the knowledge of the binding site is not required CHARMM based docking algorithm
- 18. DOCKING TOOLS FLEXIBLE DOCKING Retains receptor flexibility during docking of flexible ligands ChiFlex algorithm LibDock program Indicates the binding site where ligand polar and non-polar groups may be bound to the favourable positions of protein
- 19. DOCKING TOOLS LIGAND FIT A grid-based method for calculating receptor- ligand interaction energies, which is crucial in initial ligand shape match to the receptor binding site Consists of Definition of active site Analysis of ligand conformations Docking of ligands to a selected site Scoring of predicted poses
- 21. DOCKING TOOLS TRANSMEMBRANE PROTEIN MODELING There are many medicines that target transmembrane protein (HER2 and GABA receptor) Due to difficulties of crystallisation accurately analysing transmembrane protein is difficult Since there is influence of phospholipid bilayer a membrane force field option can be included
- 22. A modeled GABA receptor with membrane force field.
- 23. BINDING FREE ENERGY All the docking protocols discussed above do not include functions for calculating binding free energy energy of binding = energy of complex – energy of ligand – energy of receptor
- 24. FLEXIBILITY OF PROTEIN- LIGAND COMPLEX Flexibility of complex must be studied The difference in result of flexible docking and LigandFit is due to difference in flexibility of molecules, such that: Flexibility = score of LigandFit – score of flexible docking The result of molecular simulation is related to flexibility, and a positive relationship can be obtained in flexibility vs. molecular dynamics.
- 25. De novo EVOLUTION After docking program, we can modify ligands by two methods Based on active site features to identify functional groups that can establish strong interactions with the receptor. Then, functional groups can be linked Using the original ligand scaffolds to develop derivatives that can complement the receptor
- 27. LIGAND-BASED DRUG DESIGN Relies on knowledge of other molecules that bind to the biological target of interest These other molecules may be used to derive a pharmacophore model Alternatively, a QSAR relationship, in which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived QSAR may be used to predict the activity of new analogues
- 28. LIGAND-BASED DRUG DESIGN Quantitative structure-activity relationship (QSAR) CoMFA CoMSIA
- 29. QUANTITATIVE STRUCTURE- ACTIVITY RELATIONSHIP Employs statistics and analytical tools to investigate the relationship between the structures of ligands and their corresponding effects. Mathematical models are built based on structural parameters to describe Earlier 2D-QSAR, but 3D-QSAR have been adopted 3D-QSAR methodologies: CoMFA, CoMSIA
- 30. CoMFA Comparative molecular field analysis Biological activity of a molecule is dependent of the surrounding molecular fields (Steric and electrostatic fields) Has several problems
- 31. CoMSIA Comparative molecular similarity index analysis Includes more additional field properties Steric Electrostatic Hydrophobic Hydrogen bond donor Hydrogen bond acceptor Can offer a more accurate structural-activity relationship than CoMFA
- 32. CONCLUSION Molecular simulation has a vital role in drug design and CADD Fast, efficient and inexpensive tool to Discover new possible ligands against a macromolecular target Test library design ideas Identify most promising scaffolds and R groups prior to synthesis
- 33. THANK YOU