The COVID-19 pandemic has already had significant impact on the health, life-style and economy of every society worldwide. One can argue that scientists competent to contribute to our understanding of this disease have a moral obligation to do so. Our expertise is best geared towards development of therapeutics. We have therefore initiated efforts to identify chemical compounds that inhibit replication of SARS-CoV-2, the agent responsible for COVID-19.
Mpro (3CLpro) is the main protease of SARS-CoV-2. Mpro cleaves the viral precursor proteins PP1a and PP1ab into functional viral proteins. The inhibition of Mpro would therefore hinder multiple processes essential for viral replication, as it would prevent the production of the mature forms of most viral proteins .
Several groups have determined the three-dimensional structure of SARS-CoV-2 Mpro in its apo form or bound to various inhibitors [2-8]. These structures have revealed that the N-terminus of Mpro contains two domains (domain I, residues 10-99; and domain II, residues 100-184) that adopt a chymotrypsin-like fold. The active site maps at the cleft formed between these domains and contains a Cys145-His41 catalytic dyad. A total of five protein segments comprising residues 25-27 and 44-50 from domain I and residues 140-143, 165-168 and 188-190 from domain II form the walls of the active site (Figure 5A).
Comparison of eight Mpro structures determined by different groups has revealed significant flexibility in the conformation of the Mpro active site. Specifically, binding of inhibitors leads to changes in the position of the loop containing Gln189 and of the short alpha-helix containing Ser46, resulting in widening of the active site (Figure 5B).
We intend to pursue various conformers of SARS-CoV-2 Mpro for very high content in silico screening (Fig. 1C-D). Compounds identified by this screening approach will be synthesized and examined for their ability to inhibit Mpro in vitro and viral replication in cells. Collaborators with expertise in drug screening, medicinal chemistry and virology will be assisting us in these efforts.
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