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
Highlights
In December 2019, a new infectious respiratory disease severe acute respiratory syndrome caused by novel coronavirus 2 (SARS-CoV-2) emerged in Wuhan City, Hubei Province, China [1,2,3] which spread all around the world, infecting millions of people and causing thousands of death [case fatality rate (CFR): 8.8%, John Hopkins Coronavirus Resource Center, accessed 3 January 2021] [4]
The remote residues from the catalytic region of Main protease (Mpro) were perhaps thought to be non-essential for functional activity, but our computational hypothesis suggests that (i) His163, Tyr161, W1, and W2 water molecules may play an important role in tuning the changes of conformation though they are away from active site region, and (ii) they may act as catalytic partners with Cys145-His41 pair
The computational investigations are consistent with the existence of two conserved water molecules (W1 and W2) that maintain the architecture of catalytic dyad (Cys145-His41) in the ligand-free conformations of Mpro
Summary
In December 2019, a new infectious respiratory disease severe acute respiratory syndrome caused by novel coronavirus 2 (SARS-CoV-2) emerged in Wuhan City, Hubei Province, China [1,2,3] which spread all around the world, infecting millions of people and causing thousands of death [case fatality rate (CFR): 8.8%, John Hopkins Coronavirus Resource Center, accessed 3 January 2021] [4]. On March 11, 2020, the World health organization (WHO) officially announced coronavirus disease 2019 (COVID-19) as a global pandemic. SARS was appeared by infection of coronavirus (CoV) in 2002 in Guangdong, China, and this SARS-CoV was globally spread with associated with 8,096 cases and 774 deaths [5]. No specific approved drugs or vaccines are available to combat CoV or SARS-CoV-2. Few common drugs that have been prescribed as therapeutic interventions for
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