Triple Targeting of Human IMPDH and Both RdRps of SARS-CoV-2 and Rhizopus Oryzae: An in Silico Perspective

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Abstract Mucormycosis has been reported in many regions associated with SARS-CoV-2 infections during the past few months. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target in viral and fungal pathogens. Molecular docking combined with molecular dynamics simulation (MDS) is utilized to test nucleotide-based inhibitors against the RdRps of SARS-CoV-2 solved structure and Rhizopus oryzae RdRp model built in silico. Additionally, the human Inosine monophosphate dehydrogenase (IMPDH) was targeted by the same inhibitors. 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 main causing agent of mucormycosis. The binding affinities are calculated using different conformations of the RdRps after 100 ns MDS and trajectories clustering. The present 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.

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