Insect protease inhibitors; promising inhibitory compounds against SARS-CoV-2 main protease

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has adversely affected global health since its emergence in 2019. The lack of effective treatments prompted worldwide efforts to immediately develop therapeutic strategies against COVID-19. The main protease (M^pro) of SARS-CoV-2 plays a crucial role in viral replication, and therefore it serves as an attractive target for COVID-19-specific drug development. Due to the richness and diversity of insect protease inhibitors, we docked SARS-CoV-2 M^pro onto 25 publicly accessible insect-derived protease inhibitors using the ClusPro server, and the regions with high inhibitory potentials against M^pro were used to design peptides. Interactions of these inhibitory peptides with M^pro were further assessed by two directed docking programs, AutoDock and Haddock. AutoDock analysis predicted the highest binding energy (-9.39 kcal/mol) and the lowest inhibition constant (130 nM) for the peptide 1KJ0-7 derived from SGCI (Schistocerca gregaria chymotrypsin inhibitor). On the other hand, Haddock analysis resulted in the discovery of a different peptide designated 2ERW-9 from infestin, a serine protease inhibitor of Triatoma infestans, with the best docking score (-131), binding energy (-11.7 kcal/mol), and dissociation constant (2.6E-09 M) for M^pro. Furthermore, using molecular dynamic simulations, 1KJ0-7 and 2ERW-9 were demonstrated to form stable complexes with M^pro. The peptides also showed suitable drug-likeness properties compared to commercially available drugs based on Lipinski's rule. Our findings present two peptides with possible protease inhibitor activities against M^pro and further demonstrate the potential of insect-derived peptides and computer-aided methods for drug discovery.

Keywords: Docking; Main protease (M(pro)); Molecular dynamic simulation; Peptide inhibitor; SARS-CoV-2.