Quantum Dynamics and Bi Metal Force Field Parameterization Yielding Significant Antileishmanial Targets

Amid emerging drug resistance to metal inhibitors, high toxicity, and onerous drug delivery procedures, the computational design of alternate formulations encompassing functional metal-containing compounds greatly relies on large-scale atomistic simulations. Simulations particularly with Au(I), Ag, Bi(V), and Sb(V) pose a major challenge to elucidate their molecular mechanism due to the absence of force field parameters. This study thus quantum mechanically derives force field parameters of Bi(V) as an extension of the previous experimental study conducted on heteroleptic triorganobismuth(V) biscarboxylates of type [BiR₃(O₂CR')₂]. We have modeled two organo-bismuth(V) carboxylates, which are optimized and parameterized along with the famous pentavalent antimonial drug: meglumine antimoniate using quantum mechanics original Seminarian methods with the SBKJC effective core potential (ECP) basis set. Furthermore, molecular dynamics (MD) simulations of bismuth- and antimony-containing compounds in complex with two enzymes, trypanothione synthetase-amidase (TSA) and trypanothione reductase, are performed to target the (T(SH)₂) pathway at multiple points. MD simulations provide novel insights into the binding mechanism of TSA and highlight the role of a single residue Arg569 in modulating the ligand dynamics. Moreover, the presence of an ortho group in a ligand is emphasized to facilitate interactions between Arg569 and the active site residue Arg313 for higher inhibitory activity of TSA. This preliminary generation of parameters specific to bismuth validated by simulations in replica will become a preamble of future computational and experimental research work to open avenues for newer and suitable drug targets.