Binding site identification of COVID-19 main protease 3D structure by homology modeling

Marion Adebiyi, Oludayo O. Olugbara


The influx of coronavirus in 2019 (COVID-19) from Wuhan of China has led to a global pandemic, undesirable hiatus, and recorded millions of infection cases with several deaths worldwide. The strain of COVID-19 has neither known treatments nor vaccines, but recent studies have shown that a few of its enzymes may have been considered as potential drug target. Since its influx, the virus has been well-studied, but a lot is not known about its protease yet.  The purpose of this work was to identify the binding site in-silico and present 3D structure of COVID-19 main protease (Mpro) by homology modeling through multiple alignment followed by optimization and validation. The modeling was done by Swiss-Model template library and basic local alignment search tool (BLAST). The obtained homotrimer oligo-state model was verified for reliability using structural validation software such as PROCHECK, Verify3D, MolProbity and QMEAN. The HHBlits software was used to determine the structures that matched the target sequence by evolution. Best template, 6u7h.1.A was used to build a tertiary structure for Mpro with ProMod3 3.0.0 on the Swiss-Model workspace. Self-optimized prediction method with alignment (SOPMA) was applied to compute features of the secondary structure. The verification of quality of COVID-19 structure through Ramachandran plot showed an abundance of 99.3% of amino acid residues in allowed regions while 0.1% in disallowed region. The Verify3D rated the structure a 90.87% PASS of residues having an average 3D-1D score of at least 0.2, which validates a good environment profile for the COVID-19 Mpro model. The features of the secondary structure indicated that the modeled 3D structure of Mpro contains 32.05% α-helix and 37.17% random coil with 25.92 extended strand. DeepSite algorithm elucidates the binding site area that captured local patterns in the structure and exposed the surface cavity of the binding pocket of this protein. The main result of this study suggests that blocking expression of the protein may constitute an efficient approach for transmission blockage. Hence, our thought is that Mpro of COVID-19 may be considered a potential drug target. Nevertheless, more experimental analyses, verification and validation experiments will be required as a targeted drug or vaccine design against COVID-19 virus.


Binding site; COVID-19; Homology model; Main protease; 3D structure

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