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Article

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

1
Department of Chemistry, Rhodes College, 2000 North Parkway, Memphis, TN 38112, USA
2
College of Veterinary Medicine, Tuskegee University, 201 Frederick D Patterson Dr, Tuskegee, AL 36088, USA
3
Walnut Hills High School, 3250 Victory Pkwy, Cincinnati, OH 45207, USA
4
National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA
5
Department of BioMolecular Sciences, Schools of Pharmacy, University of Mississippi, University, MS 38677, USA
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(9), 942; https://doi.org/10.3390/v12090942
Received: 24 July 2020 / Revised: 14 August 2020 / Accepted: 22 August 2020 / Published: 26 August 2020
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. View Full-Text
Keywords: coronaviruses; molecular docking; inhibitor design; molecular interactions; COVID-19; molecular dynamics; SARS-CoV-2 main protease; SARS-CoV-2 Mpro coronaviruses; molecular docking; inhibitor design; molecular interactions; COVID-19; molecular dynamics; SARS-CoV-2 main protease; SARS-CoV-2 Mpro
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MDPI and ACS Style

Stoddard, S.V.; Stoddard, S.D.; Oelkers, B.K.; Fitts, K.; Whalum, K.; Whalum, K.; Hemphill, A.D.; Manikonda, J.; Martinez, L.M.; Riley, E.G.; Roof, C.M.; Sarwar, N.; Thomas, D.M.; Ulmer, E.; Wallace, F.E.; Pandey, P.; Roy, S. Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site. Viruses 2020, 12, 942. https://doi.org/10.3390/v12090942

AMA Style

Stoddard SV, Stoddard SD, Oelkers BK, Fitts K, Whalum K, Whalum K, Hemphill AD, Manikonda J, Martinez LM, Riley EG, Roof CM, Sarwar N, Thomas DM, Ulmer E, Wallace FE, Pandey P, Roy S. Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site. Viruses. 2020; 12(9):942. https://doi.org/10.3390/v12090942

Chicago/Turabian Style

Stoddard, Shana V., Serena D. Stoddard, Benjamin K. Oelkers, Kennedi Fitts, Kellen Whalum, Kaylah Whalum, Alexander D. Hemphill, Jithin Manikonda, Linda M. Martinez, Elizabeth G. Riley, Caroline M. Roof, Nowreen Sarwar, Doni M. Thomas, Emily Ulmer, Felissa E. Wallace, Pankaj Pandey, and Sudeshna Roy. 2020. "Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site" Viruses 12, no. 9: 942. https://doi.org/10.3390/v12090942

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