Computational Studies to Identify Potential Main Protease Inhibitors for SARS-CoV-19

Abstract

<jats:p>The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.</jats:p>

Pyrazolone-type compounds: synthesis andin silicoassessment of antiviral potential against key viral proteins of SARS-CoV-2

“…9 The SARS-CoV-2 comprises two overlapping polyproteins (pp1a and pp1ab) encoded with $30 kb RNA genome, which cleavage is essential for replication and transcription processes. [10][11][12][13] These cleavage processes are regulated by non-structural viral proteins, such as the main protease M pro (also known as 3chymotrypsin-like protease 3CL pro ) and papain-like protease PL pro . [8][9][10][11] The M pro protein is a homodimer structure, where the substrate-binding site consists of ve sub-pockets responsible for the proteolytic activity through a multi-step mechanism, involving an uncommon Cys145-His41 catalytical dyad with the help of a water molecule.…”

“…14 Hence, these atypical features and the engagement in the viral lifecycle designated M pro as an attractive antiviral target. [10][11][12]15 Similarly, the cysteine protease (PL pro ) is engaged in multiple processes linked with viral maturation and spread, as well as in mechanisms of evasion host antiviral immune response. 16,17 On the other hand, inhibition of the receptor-binding processes and blocking the entry into the host cell are also part of antiviral strategies.…”

“…[21][22][23][24] Molecular docking is also identied as a cost-effective and less time-consuming method for the search of promising antiviral candidates, particularly against SARS-CoV-2. 8,9,12,23,[25][26][27] Such molecular docking analysis identied various potential compounds that can interact with M pro and S proteins of virus SARS-CoV-2, including pyrazolone-type compounds. 28,29 Moreover, pyrazolone-based compounds were investigated on the SARS-CoV and MERS-CoV proteases and designated as a good base for the development of antiviral agents.…”

“…8,9 Compound interacting with catalytic amino acid residues of these subpockets can inhibit the proteolytic action of SARS-CoV-2 main protease. 12 Furthermore, the M pro divides the polypeptide chain after Gln residue, unlike all known human proteases. 14 Hence, these atypical features and the engagement in the viral lifecycle designated M pro as an attractive antiviral target.…”