Drug design and repurposing with DockThor-VS web server focusing on SARS-CoV-2 therapeutic targets and their non-synonym variants.

The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br .

Highly Flexible Ligand Docking: Benchmarking of the DockThor Program on the LEADS-PEP Protein-Peptide Data Set.

Protein-peptide interactions play a crucial role in many cellular and biological functions, which justify the increasing interest in the development of peptide-based drugs. However, predicting experimental binding modes and affinities in protein-peptide docking remains a great challenge for most docking programs due to some particularities of this class of ligands, such as the high degree of flexibility. In this paper, we present the performance of the DockThor program on the LEADS-PEP data set, a benchmarking set composed of 53 diverse protein-peptide complexes with peptides ranging from 3 to 12 residues and with up to 51 rotatable bonds. The DockThor performance for pose prediction on redocking studies was compared with some state-of-the-art docking programs that were also evaluated on the LEADS-PEP data set, AutoDock, AutoDock Vina, Surflex, GOLD, Glide, rDock, and DINC, as well as with the task-specific docking protocol HPepDock. Our results indicate that DockThor could dock 40% of the cases with an overall backbone RMSD below 2.5 Å when the top-scored docking pose was considered, exhibiting similar results to Glide and outperforming other protein-ligand docking programs, whereas rDock and HPepDock achieved superior results. Assessing the docking poses closest to the crystal structure (i.e., best-RMSD pose), DockThor achieved a success rate of 60% in pose prediction. Due to the great overall performance of handling peptidic compounds, the DockThor program can be considered as suitable for docking highly flexible and challenging ligands, with up to 40 rotatable bonds. DockThor is freely available as a virtual screening Web server at https://www.dockthor.lncc.br/ .