J Chem Inf Model - Structure-based virtual screening approach for discovery of covalently bound ligands.

Tópicos

{ compound(1573) activ(1297) structur(1058) }
{ bind(1733) structur(1185) ligand(1036) }
{ drug(1928) target(777) effect(648) }
{ algorithm(1844) comput(1787) effici(935) }
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Resumo

We present a fast and effective covalent docking approach suitable for large-scale virtual screening (VS). We applied this method to four targets (HCV NS3 protease, Cathepsin K, EGFR, and XPO1) with known crystal structures and known covalent inhibitors. We implemented a customized "VS mode" of the Schr?dinger Covalent Docking algorithm (CovDock), which we refer to as CovDock-VS. Known actives and target-specific sets of decoys were docked to selected X-ray structures, and poses were filtered based on noncovalent protein-ligand interactions known to be important for activity. We were able to retrieve 71%, 72%, and 77% of the known actives for Cathepsin K, HCV NS3 protease, and EGFR within 5% of the decoy library, respectively. With the more challenging XPO1 target, where no specific interactions with the protein could be used for postprocessing of the docking results, we were able to retrieve 95% of the actives within 30% of the decoy library and achieved an early enrichment factor (EF1%) of 33. The poses of the known actives bound to existing crystal structures of 4 targets were predicted with an average RMSD of 1.9 ?. To the best of our knowledge, CovDock-VS is the first fully automated tool for efficient virtual screening of covalent inhibitors. Importantly, CovDock-VS can handle multiple chemical reactions within the same library, only requiring a generic SMARTS-based predefinition of the reaction. CovDock-VS provides a fast and accurate way of differentiating actives from decoys without significantly deteriorating the accuracy of the predicted poses for covalent protein-ligand complexes. Therefore, we propose CovDock-VS as an efficient structure-based virtual screening method for discovery of novel and diverse covalent ligands.

Resumo Limpo

present fast effect coval dock approach suitabl largescal virtual screen vs appli method four target hcv ns proteas cathepsin k egfr xpo known crystal structur known coval inhibitor implement custom vs mode schrdinger coval dock algorithm covdock refer covdockv known activ targetspecif set decoy dock select xray structur pose filter base noncoval proteinligand interact known import activ abl retriev known activ cathepsin k hcv ns proteas egfr within decoy librari respect challeng xpo target specif interact protein use postprocess dock result abl retriev activ within decoy librari achiev earli enrich factor ef pose known activ bound exist crystal structur target predict averag rmsd best knowledg covdockv first fulli autom tool effici virtual screen coval inhibitor import covdockv can handl multipl chemic reaction within librari requir generic smartsbas predefinit reaction covdockv provid fast accur way differenti activ decoy without signific deterior accuraci predict pose coval proteinligand complex therefor propos covdockv effici structurebas virtual screen method discoveri novel divers coval ligand

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