Topological Analysis of SARS CoV-2 Main Protease

Abstract

There is an urgent necessity of effective medication against SARS CoV-2, which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mpro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here we report that as average SARS CoV-2 Mpro is 1900% more sensitive than SARS CoV-1 Mpro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mpro to structural perturbations is located exactly around the catalytic site Cys-145, and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro. The main protease of the new coronavirus SARS CoV-2 represents one of the most important targets for the antiviral pharmacological actions againsts COVID-19. This enzyme is essential for the virus due to its proteolytic processing of polyproteins. Here we discover that the main protease of SARS CoV-2 is topologically very similar to that of the SARS CoV-1. This is not surprising taking into account that both proteases differ only in 12 amino acids. However, we remarkable found a topological property of SARS CoV-2 that has increased in more than 1900% repect to its SARS CoV-1 analogue. This property reflects the capacity of the new protease of transmitting perturbations across its domains using long-range interactions. Also remarkable is the fact that the amino acids displaying such increased sensitivity to perturbations are around the binding site of the new protease, and close to its catalytic site. We also show that this sensititivy to perturbations is related to the effects of powerful protease inhibitors. In fact, the strongest inhibitors of the SARS CoV-2 main protease are those that produce the least change of this capacity of transmitting perturbations across the protein. We think that these findings may help in the design of new potent anti-SARS CoV-2 inhibitors.