Triple targeting of human IMPDH, SARS-CoV-2 RdRp, and Rhizopus oryzae RdRp: An in silico perspective

Abstract

Objectives: Mucormycosis has been reported associated with SARS-CoV-2 infections during the last year. The viral RNA-dependent RNA polymerase (RdRp) was proved to be a critical protein target in viral and fungal pathogens. The human inosine monophosphate dehydrogenase (IMPDH) is an evolved antiviral and antimicrobial therapeutic target. The aim is to triple-hit the viral and fungal RdRps and the human IMPDH. Methods: In the current study, molecular docking combined with molecular dynamics simulation (MDS) is utilized to test nucleotide inhibitors against the RdRps of SARS-CoV-2 and Rhizopus oryzae (the main causing agent of mucormycosis) RdRp. Additionally, the same inhibitors targeted the human Inosine monophosphate dehydrogenase (IMPDH). Results: The results reveal a comparable binding affinity of four nucleotide derivatives compared to remdesivir and sofosbuvir against both IMPDH and the RdRps of SARS-CoV-2 and Rhizopus oryzae. The binding affinities are calculated using different conformations of the RdRps after 100 ns MDS and trajectories clustering. Conclusions: The current study suggests the triple inhibition potential of four nucleotide inhibitors against SARS-CoV-2 & R. oryzae RdRps and the human IMPDH, while experimental validation is yet to be performed.