POTENTIAL PROTEASE INHIBITORS’ COMBINATIONS FOR THE TREATMENT OF COVID-19 BASED ON IN-SILICO ANALYSIS OF 3CL-PROTEASE BINDING SITES

Abstract

COVID-19 is an ongoing outbreak of viral pneumonia that was first discovered in China by the end of 2019. Since then, COVID-19 has spread out from China across the globe. Therefore, there is an urgent need to find an immediate effective therapy in order to halt the spread of this virus. Many studies have been conducted over the past year focusing on the repurposing of FDA approved drugs to manage COVID-19 infections. Such drugs include the combination of HIV protease inhibitors lopinavir and ritonavir which were reported to target COVID-19 protease. In the current study, various binding sites within the COVID-19 3CL-protease were explored using PrankWeb and DeepSite servers to identify potential combinations of inhibitors which could contribute to a successful management for the clinical studies. Results show that the four binding sites of 3CL protease have the ability to bind with the selected inhibitors with varying affinities. Molecular docking, dynamics, and mechanics simulations show distinct results for the inhibitors (ledipasvir and velpatasvir) within these four pockets. Moreover, although these antivirals can be competitive inhibitors for the 3CL-protease, yet they can bind to other potential allosteric binding sites which facilitates and allows medical professionals to study combinations of these drugs with other inhibitors. We also suggest a combination of an HIV-protease inhibitors between either of indinavir, nelfinavir, ciluprevir, saquinavir, or darunavir with ledipasvir or velpatasvir which could be considered for further clinical investigations against COVID-19.