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DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins.

ABSTRACT: An unprecedented research effort has been undertaken in response to the ongoing COVID-19 pandemic. This has included the determination of hundreds of crystallographic structures of SARS-CoV-2 proteins, and numerous virtual screening projects searching large compound libraries for potential drug inhibitors. Unfortunately, these initiatives have had very limited success in producing effective inhibitors against SARS-CoV-2 proteins. A reason might be an often overlooked factor in these computational efforts: receptor flexibility. To address this issue we have implemented a computational tool for ensemble docking with SARS-CoV-2 proteins. We have extracted representative ensembles of protein conformations from the Protein Data Bank and from in silico molecular dynamics simulations. Twelve pre-computed ensembles of SARS-CoV-2 protein conformations have now been made available for ensemble docking via a user-friendly webserver called DINC-COVID (dinc-covid.kavrakilab.org). We have validated DINC-COVID using data on tested inhibitors of two SARS-CoV-2 proteins, obtaining good correlations between docking-derived binding energies and experimentally-determined binding affinities. Some of the best results have been obtained on a dataset of large ligands resolved via room temperature crystallography, and therefore capturing alternative receptor conformations. In addition, we have shown that the ensembles available in DINC-COVID capture different ranges of receptor flexibility, and that this diversity is useful in finding alternative binding modes of ligands. Overall, our work highlights the importance of accounting for receptor flexibility in docking studies, and provides a platform for the identification of new inhibitors against SARS-CoV-2 proteins.

SUBMITTER: Hall-Swan S

PROVIDER: S-EPMC8518241 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 Mpro), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 Mpro active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 Mpro crystal structures. Several key preferences for strong binding to the four subsites (S1, S1', S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 -log10(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 Mpro inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 -log10(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 Mpro [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals.

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DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins.

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