Importance of glutamine 189 flexibility in SARS-CoV-2 main protease: Lesson learned from in silico virtual screening of ChEMBL database and molecular dynamics

The current global pandemic outbreak of COVID-19, caused by the SARS-CoV-2, strikes an invincible damage to both daily life and the global economy. WHO guidelines for COVID-19 clinical management includes infection control and prevention, social distancing and supportive care using supplemental oxygen and mechanical ventilator support. Currently, evolving researches and clinical reports regarding infected patients with SARS-CoV-2 suggest a potential list of repurposed drugs that may produce appropriate pharmacological therapeutic efficacies in treating COVID-19 infected patients. In this study, we performed virtual screening and evaluated the obtained results of US-FDA approved small molecular database library (302 drug molecule) against two important different protein targets in COVID-19. Best compounds in molecular docking were used as a training set for generation of two different pharmacophores. The obtained pharmacophores were employed for virtual screening of ChEMBL database. The filtered compounds were clustered using Finger print model to obtain two compounds that will be subjected to molecular docking simulations against the two targets. Compounds complexes with SARS-CoV-2 main protease and S-protein were studied using molecular dynamics (MD) simulation. MD simulation studies suggest the potential inhibitory activity of ChEMBL398869 against SARS-CoV-2 main protease and restress the importance of Gln189 flexibility in inhibitors recognition through increasing S2 subsite plasticity.