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The Possible Molecular Mechanism of SARS-CoV-2 Main Protease: New Structural Insights from Computational Methods

Alvea Tasneem, Gyan Prakash Rai, Saima Reyaz, Hridoy R. Bairagya

Abstract


Main protease (Mpro) is one of the key enzymes in the life cycle of SARS-CoV-2 that plays a pivotal role in mediating viral replication, transcription, and makes it an attractive drug target for this virus.  The catalytic site of this enzyme comprises of a dyad His41 and Cys145 and lacks the third catalytic residue, which is replaced by a stable water molecule (W). The computational structural analysis on crystal data for Mpro protein suggests that W1, W2, His163, and Tyr161 may also play a vital role in the activity of this enzyme and they may act as catalytic partners along with Cys(145)-His(41) catalytic dyad. The thiolate–imidazolium ion-pair between Cys145 (-SH---NE2-) His41 and Cys145 (-SH---NE2-) His163 have been stabilized by W1 (with W2) and Tyr161, respectively. Therefore, unique interactions of W2---W1---ND1-His41-NE2---SH-Cys145 or Cys145-SH---NE2-His163-ND1---OH-Tyr161 in Mpro serve as an excellent drug target for this enzyme and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site, its shape, and complementarities. Our computational hypothesis suggests two essential clues that may be implemented to design a new inhibitor for Mpro protein. The strategies are: (i) ligand should be occupied either W1 or W2 or both of these position to displace these water molecules from the catalytic region, and (ii) ligand should be made H-bonds with Cys145 (-SH), His41 (NE2/ND1) and His163(NE2) to inhibit Mpro. The results from this computational study could be of interest to the experimental community and also provide a testable hypothesis for experimental validation.

 

Doi: 10.28991/SciMedJ-2020-02-SI-11

Full Text: PDF


Keywords


Catalytic Mechanism of Mpro Protein; Role of His163, Tyr161 and Water Molecules; Inhibitor Binding Strategies of Mpro; SARS-CoV-2.

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DOI: 10.28991/SciMedJ-2020-02-SI-11

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