Structure-based virtual screening approach for discovery of covalently bound ligands.
J Chem Inf Model
; 54(7): 1941-50, 2014 Jul 28.
Article
en En
| MEDLINE
| ID: mdl-24932913
ABSTRACT
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 Schrödinger 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 Å. 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Evaluación Preclínica de Medicamentos
/
Simulación del Acoplamiento Molecular
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos