Ensemble Docking Interrogates Structural Determinants of Ligand-Protein Interactions

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At the interface of chemistry and biology proteins are interrogated using libraries of small molecules to deduce structural determinants of substrate recognition, the fundamentals of structure/activity relationship (SAR), or the mechanism of modulation. It is our hypothesis that accuracy of small molecule-protein docking can be improved if simultaneously the energetics of the interaction and the structure-activity relations are identified. This approach will counter-balance the inaccuracy of the comparative model. It is therefore the objective of the present proposal to develop an algorithm ‘ROSETTALIGANDENSEMBLE’ that docks an ensemble of small molecules with known affinities/activities into a comparative model of the membrane protein. We will apply the method to the identification of structural determinants required for agonistic and inverse agonistic ligand properties at the ADP receptor P2Y12. Further, the algorithm will be employed to study the mechanism of allosteric modulation of the neuropeptide Y4 receptor. Both GPCR systems have been selected as model scenarios to study small molecule-GPCR interaction as not only focused libraries of small molecules with known biological activities are available but an immediate experimental feedback loop has been setup to test novel ligands but also use receptor variants to determine interaction sites.