Predictive modelling of GPCR druggable allosteric sites

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Antonella Ciancetta and Irina G. Tikhonova

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School of Pharmacy, Queen's University Belfast

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G protein coupled-receptors (GPCRs) are the most successful class of drug targets in the human genome. Around 40% prescription drugs provide their therapeutic action through GPCRs. GPCRs function can be controlled by small molecule ligands binding to allosteric sites, which are distinct from orthosteric sites binding endogenous ligands. These allosteric drugs are meant to be are more selective and less toxic than orthosteric drugs. The discovery of the allosteric drugs is difficult and to date has largely been achieved through lengthy and costly high-throughput screening campaigns. The recent availability of GPCRs in complex with allosteric ligands helps to start allosteric drug search through structure-based computational approaches.

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MIDAS focuses on the development of a computational methodology to search allosteric binding sites using molecular simulations and fragment-based drug design approaches. The project uses four receptors as case studies to optimize computational protocols. Computational protocols are further validated via collaboration with pharmacologists. The outcome of the action will foster the search for a new class of GPCR allosteric drugs.  

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Further details to be announced.