Abstract
Mucormycosis (or black fungus infection) is a life-threatening, but rare fungal infection with predominant occurrence in immunosuppressed patients following the SARS-CoV-2 infection. Rhizopus oryzae (R. O.) causes about 70% of all cases of mucormycosis. RNA dependent RNA polymerase (RdRp) is a key fungal protein implicated in the genome replication and multiplication of R. oryzae. In view of biological significance of resveratrol (RES), rich in grape skin extract, on various microbial infections and inflammatory diseases including gum infections and periodontitis, our present study was aimed at in silico investigation of RES and its two natural analogues, piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene, PIC), and 3,5,4'-trimethoxy-trans-stilbene (TMS) for their development as successful antifungal agents targeting the R. O. specific RdRp to combat the deadly mucormycosis. Due to the unavailability of the three-dimensional structure of R. O. RdRp in the Protein Database Bank (PDB), the protein structure of RdRp was modeled using the target sequence of RT/Duplex (Set-Met) (PDB ID: 6AR3, 3.41 angstrom) by homology modeling. Using the modeled structure of R. O. RdRp, docking and molecular dynamics (MD) simulation studies were carried out in Schrodinger suite version 2021-2 software. The findings of docking, MD simulations and MM-PBSA binding energies conclude that the RES, PIC and TMS possess predictable and stable binding affinity/interactions to the R. O. RdRp. These bioactive compounds could potentially inhibit the activity of R. O. RdRp. Further, density function theory (DFT) analysis (B3LYP, 6-311 G* basis set) was performed, and results of DFT analysis indicate that the compound PIC could be a more potential inhibitor for R. O. RdRp over RES. In in silico drug-likeness and ADMET prediction studies, all of the compounds exhibited acceptable drug-likeness, the Lipinski's rule of five and pharmacokinetic parameters. Finally, it can be concluded that RES and its two natural analogues, PIC and TMS are the potential inhibitors of R. O. RdRp based on docking, MD and DFT studies.