J Chem Inf Model - Selecting an optimal number of binding site waters to improve virtual screening enrichments against the adenosine A2A receptor.


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A major challenge in structure-based virtual screening (VS) involves the treatment of explicit water molecules during docking in order to improve the enrichment of active compounds over decoys. Here we have investigated this in the context of the adenosine A2A receptor, where water molecules have previously been shown to be important for achieving high enrichment rates with docking, and where the positions of some binding site waters are known from a high-resolution crystal structure. The effect of these waters (both their presence and orientations) on VS enrichment was assessed using a carefully curated set of 299 high affinity A2A antagonists and 17,337 decoys. We show that including certain crystal waters greatly improves VS enrichment and that optimization of water hydrogen positions is needed in order to achieve the best results. We also show that waters derived from a molecular dynamics simulation - without any knowledge of crystallographic waters - can improve enrichments to a similar degree as the crystallographic waters, which makes this strategy applicable to structures without experimental knowledge of water positions. Finally, we used decision trees to select an ensemble of structures with different water molecule positions and orientations that outperforms any single structure with water molecules. The approach presented here is validated against independent test sets of A2A receptor antagonists and decoys from the literature. In general, this water optimization strategy could be applied to any target with waters-mediated protein-ligand interactions.

Resumo Limpo

major challeng structurebas virtual screen vs involv treatment explicit water molecul dock order improv enrich activ compound decoy investig context adenosin aa receptor water molecul previous shown import achiev high enrich rate dock posit bind site water known highresolut crystal structur effect water presenc orient vs enrich assess use care curat set high affin aa antagonist decoy show includ certain crystal water great improv vs enrich optim water hydrogen posit need order achiev best result also show water deriv molecular dynam simul without knowledg crystallograph water can improv enrich similar degre crystallograph water make strategi applic structur without experiment knowledg water posit final use decis tree select ensembl structur differ water molecul posit orient outperform singl structur water molecul approach present valid independ test set aa receptor antagonist decoy literatur general water optim strategi appli target watersmedi proteinligand interact

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