Structure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands

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.

A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

“…The compounds showing the higher docking scores were then subjected to another virtual screening specifically designed to identify compounds able to covalently target the active site residue C113. To this aim, a covalent docking approach using the CovDock-VS method17 was exploited. These approaches yielded around one hundred possible PIN1 covalent binders that were tested afterwards for cytotoxicity against melanoma A375 cells using the MTT viability assay.…”

“…Virtual Screening of this collection was performed using a covalent docking approach suitable for large-scale virtual screening (VS) called CovDock-VS method previously described17 on the structure of the catalytic pocket of PIN1. Briefly, compounds were prepared using the Virtual Screening Workflow (VSW) ligand preparation tab in Maestro (Maestro v9.2.…”

Covalent inhibition of protein tyrosine phosphatases

“…The strategy of introducing an electrophile onto a highly potent and selective inhibitor of a particular target PTP, based on X-ray crystal structure studies or docking studies, could provide selective and potent inactivators of PTPs. Computational tools such as CovalentDock, 182 GOLD, 183 CovDock-VS, 184 Autodock, 185 Glide, 186 CovDock, 187 etc. are available to aid researchers to design covalent inhibitors with drug-like properties.…”

A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

“…We employed the covalent docking protocol CovDock2627 implemented in the Schrödinger Suite to visualize possible conformational states of the C285 thioether resulting from the reaction with 1 . CovDock uses different tools of the Schrödinger Suite to mimic distinct stages of covalent inhibitor binding.…”