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Docking based screening of drugs.
- 1. Docking based Screening HimanshuYadav(201408006) M. Pharm (Pharmacology) SGT University
- 2. Virtual Screening (VS) •The virtual screening approach (VS) involves the rapid assessment of large libraries of chemical compounds in order to guide the selection of lead candidates using computer based techniques • The VS approach is faster and less expensive and can be used to select compounds for a particular binding site.
- 3. Three main elementshave to be taken into account to evaluate the docking-based VS methods: • The quality of the obtained docking poses. • The ability of the methods to discriminate between active and inactive compounds. • The required time.
- 4. Classification All VS techniquescan be roughly classified as ligand- or receptor-based methods. • The ligand-based methods use information provided by a compound or set of compounds that are known to bind to the desired target to extract other compounds with similar properties from existing databases. • Examples of ligand-based methods include similarity searching, quantitative structure-activity relationship (QSAR) models, fingerprint and pharmacophore searching.
- 5. Classification • Receptor basedmethods use knowledge of the 3D structure of the target (obtained by means of X-ray crystallography, NMR experiments, or predicted by homology modelling techniques) to search for compounds that may favourably interact with the target. • The most important component of the receptor-based VS method is the docking approach
- 7. Ligand based methods •Similarity searching- The similar property principle states that structurally similar molecules tend to have similar properties. • Pharmacophore- A pharmacophore is the ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target structure and to trigger (or to block) its biological response.
- 8. Pharmacophore generation methods •Pharmacophoric features in each ligand identified – Donors, acceptors, hydrophobic groups,... – Often SMARTs-based to allow user-definitions • Ligands aligned such that corresponding features are overlaid • Conformational space explored – On-the-fly eg using a genetic algorithm – Generating ensemble of conformations with each conformer considered in turn • Given the undetermined nature of the problem it is unlikely that a single correct solution will be found • Pharmacophore hypotheses are scored – eg number of features, goodness of fit to features, conformational energy, volume of the overlay, rarity of the pharmacophore,....
- 9. Machine Learning methods Structure-ActivityRelationship Modelling • Use knowledge of known active and known inactive compounds to build a predictive model • Quantitative-Structure Activity Relationships (QSARs) – Long established (Hansch analysis, Free-Wilson analysis) – Generally restricted to small, homogeneous datasets eg lead optimisation • Structure-Activity Relationships (SARs) – “Activity” data is usually treated qualitatively – Can be used with data consisting of diverse structural classes and multiple binding modes – Some resistance to noisy data (HTS data) – Resulting models used to prioritise compounds for lead finding (not to identify candidates or drugs)
- 10. OTHER DOCKING-BASED VSMETHODS
- 11. OTHER DOCKING-BASED VSMETHODS 1. Classical Docking based VS studies 2. Pharmacophore/Docking VS Studies 3. Docking/Pharmacophore VS studies 4. Fragment Docking-Based Approach 5. New Docking-Based VS Methods
- 12. OTHER DOCKING-BASED VSMETHODS • Classical Docking based VS studies-It begins with the use of a 3D- structure of the target protein, and then using the docking software, compounds stored in databases are docked inside the target protein. Using scoring functions that analyse the docking results, ligands that are believed to interact better inside the receptor are selected. • Pharmacophore/Docking VS Studies-A pharmacophore represents the spatial arrangement of key structural features of a set of known ligands or of the target receptor.
- 13. OTHER DOCKING-BASED VSMETHODS • Docking/Pharmacophore VS studies-In the case of the Docking/Pharmacophore VS studies, the qualitative filter is constituted by a pharmacophore model that filters the best ranked solutions evaluated using scoring functions • Fragment Docking-Based Approach-This method relies on identification by means of docking-based VS techniques of low molecular weight compounds that possess a lowaffinity for the chosen target and attempts to build up active ligands by linking or optimizing these small fragments.
- 14. OTHER DOCKING-BASED VSMETHODS • New Docking-Based VS Methods- This methodology begins with the identification of a template designed to fit into part of the active site and with attachment points to which substituents can be applied using simple chemical reactions
- 15. Uses Virtual screening canbe used to − Select compounds for screening from in-house databases − Choose compounds to purchase from external suppliers − Decide which compounds to synthesise next
- 16. References • Tuccinardi T.Docking-based virtual screening: recent developments. Comb Chem High Throughput Screen. 2009 Mar;12(3):303-14. doi: 10.2174/138620709787581666. PMID: 19275536. • Val Gillet. Ligand-Based and Structure-Based Virtual Screening. The University of Sheffield
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