Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents

The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. M(pro) is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression. The M(pro) enzyme seems to have several allosteric sites that can hinder the enzyme catalytic activity. Furthermore, some of these allosteric sites are located at or nearby the dimerization interface which is essential for the overall M(pro) activity. In this review paper, we investigate the potential of the M(pro) allosteric site to act as a drug target, especially since they interestingly appear to be resistant to mutation. The work is illustrated through three subsequent sections: First, the two main categories of M(pro) allosteric sites have been explained and discussed. Second, a total of six pockets have been studied and evaluated for their druggability and cavity characteristics. Third, the experimental and computational attempts for the discovery of new allosteric inhibitors have been illustrated and discussed. To sum up, this review paper gives a detailed insight into the feasibility of developing new M(pro) inhibitors to act as a potential treatment for the COVID-19 disease.