Triple Inhibition of SARS‐CoV‐2 by Rhenium(I) Acetylacetonato Tricarbonyl Phosphine Complexes: Structural Features, DFT Calculations, HS Analysis and <i>In Silico</i> Molecular Docking Study

Abstract

Abstract To gain insights into the activity of metal‐based drugs against SARS‐CoV‐2, five rhenium complexes, namely fac ‐[Re(CO) 3 (acac)(PPh 2 Cy)] (I), fac ‐[Re(CO) 3 (acac)(PPhCy 2 )] (II), fac ‐[Re(CO) 3 (acac)(PCy 3 )] (III), fac ‐[Re(CO) 3 (acac)(P( m ‐tolyl) 3 )] (IV), and fac ‐[Re(CO) 3 (acac)(P( p ‐tolyl) 3 )] (V), with acac=acetylacetonato, PPh 2 Cy=cyclohexyldiphenylphosphine, PPhCy 2 =dicyclohexylphenylphosphine, PCy 3 =tricyclohexylphosphine, P( m ‐tolyl) 3 =tri( m ‐tolyl)phosphine, and P( p ‐tolyl) 3 =tri( p ‐tolyl)phosphine, were docked in the binding pockets of main protease, spike glycoprotein, and RNA‐dependent RNA polymerase. The resulting binding sites revealed potent SARS‐CoV‐2 inhibition, resulting from the formation of classical N−H⋅⋅⋅O and O−H⋅⋅⋅O hydrogen bonds, carbon C−H⋅⋅⋅O H‐bonds, hydrophobic contacts, as well as non‐conventional interactions such as weak C−H⋅⋅⋅N interactions, H⋅⋅⋅H, C⋅⋅⋅H/H⋅⋅⋅C, C⋅⋅⋅ lp / lp ⋅⋅⋅C and lp ⋅⋅⋅ lp contacts, cation‐π interactions and π⋅⋅⋅π stacking in the targets’ binding pockets. Moreover, we have optimized the molecular structures of these compounds using DFT methods and correlated them correspondingly to their crystal structures. We have estimated and evaluated the associated frontier molecular orbitals, as well as the global reactivity descriptors for which we have discussed the compounds’ reactivity. We have also examined intermolecular interactions by carrying out a Hirshfeld surface (HS) analysis, which showed the presence of C−H⋅⋅⋅H−C, C−H⋅⋅⋅C interactions, C−H⋅⋅⋅O non‐classical hydrogen bonds and π⋅⋅⋅π stacking, as well as non‐conventional π⋅⋅⋅ lp and lp ⋅⋅⋅ lp interactions.