Potential Inhibitors for SARS-CoV-2 Main Protease

Disciplines

Biochemistry

Abstract (300 words maximum)

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was the cause of the coronavirus pandemic of 2019. Attempts to target this virus focus on the main protease (Mpro), as it plays a major role in the processing of polyproteins made from translated viral RNA. As a course-based undergraduate research experience (CURE) project, our group took advantage of known protease inhibitors from the University of Nebraska Medical Center’s Antimicrobial Peptide Database (APD) to propose three protease inhibitors that have the potential to inhibit Mpro. Function of Mpro is dependent on a catalytic dyad between His41 and Cys145; this was a site of interest when analyzing potential inhibitors. Using Hdock and pymol, the theoretical interactions between these potential inhibitors and Mpro were analyzed and tabulated to determine the suitability for potential therapeutic use. The potential inhibitors investigated were 1YP8, P0C2A8, 2LYF, and 3OTJ. These peptides were hypothesized to be potential inhibitors of Mpro for the following reasons: peptides 1YP8, P0C2A8, and 2LYF are known protease inhibitors with anti-HIV activity, and HIV protease inhibitors have been shown to inhibit Mpro; 3OTJ is a known protease inhibitor that, due to its large size, could inhibit the substrate binding or enzymatic function. According to Hdock, the modeled docking scores were -205.75, -222.55, -213.42, and -321.83 respectively. A more negative docking score correlated with a higher possible binding model. And the confidence scores were 0.7531, 0.8102, 0.7805, and 0.9688, where roughly any number greater than 0.7 indicates that Mpro and the potential inhibitor are very likely to bind. Future studies would involve synthesizing these peptides to experimentally determine if these peptides bind, and their subsequent effect on the catalytic activity of Mpro.

Academic department under which the project should be listed

CSM - Chemistry and Biochemistry

Primary Investigator (PI) Name

Rajnish Singh

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Potential Inhibitors for SARS-CoV-2 Main Protease

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was the cause of the coronavirus pandemic of 2019. Attempts to target this virus focus on the main protease (Mpro), as it plays a major role in the processing of polyproteins made from translated viral RNA. As a course-based undergraduate research experience (CURE) project, our group took advantage of known protease inhibitors from the University of Nebraska Medical Center’s Antimicrobial Peptide Database (APD) to propose three protease inhibitors that have the potential to inhibit Mpro. Function of Mpro is dependent on a catalytic dyad between His41 and Cys145; this was a site of interest when analyzing potential inhibitors. Using Hdock and pymol, the theoretical interactions between these potential inhibitors and Mpro were analyzed and tabulated to determine the suitability for potential therapeutic use. The potential inhibitors investigated were 1YP8, P0C2A8, 2LYF, and 3OTJ. These peptides were hypothesized to be potential inhibitors of Mpro for the following reasons: peptides 1YP8, P0C2A8, and 2LYF are known protease inhibitors with anti-HIV activity, and HIV protease inhibitors have been shown to inhibit Mpro; 3OTJ is a known protease inhibitor that, due to its large size, could inhibit the substrate binding or enzymatic function. According to Hdock, the modeled docking scores were -205.75, -222.55, -213.42, and -321.83 respectively. A more negative docking score correlated with a higher possible binding model. And the confidence scores were 0.7531, 0.8102, 0.7805, and 0.9688, where roughly any number greater than 0.7 indicates that Mpro and the potential inhibitor are very likely to bind. Future studies would involve synthesizing these peptides to experimentally determine if these peptides bind, and their subsequent effect on the catalytic activity of Mpro.