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

Area of Science:

• Computational chemistry and drug discovery.
• Development of novel metal-based therapeutic agents.

Background:

• Emerging drug resistance and toxicity necessitate new therapeutic strategies.
• Lack of force field parameters hinders atomistic simulations for metal-containing drugs like Au(I), Ag, Bi(V), and Sb(V).

Purpose of the Study:

• To derive quantum mechanically force field parameters for bismuth(V) compounds.
• To investigate the molecular mechanisms of bismuth and antimony compounds against parasitic enzymes using molecular dynamics (MD) simulations.

Main Methods:

• Quantum mechanics calculations using Seminarian methods and SBKJC effective core potential (ECP) basis set.
• Optimization and parameterization of organo-bismuth(V) carboxylates and meglumine antimoniate.
• Molecular dynamics (MD) simulations of drug-enzyme complexes targeting the (T(SH)2) pathway.

Main Results:

• Successfully generated force field parameters for bismuth(V) compounds.
• MD simulations provided insights into the binding mechanism of TSA, highlighting the role of Arg569.
• Identified the importance of ortho groups in ligands for enhanced TSA inhibition via interactions with Arg569 and Arg313.

Conclusions:

• The generated bismuth parameters are validated by simulations, paving the way for future computational and experimental research.
• This work facilitates the design of novel bismuth-based drugs with improved efficacy and delivery.
• The findings offer new avenues for developing targeted therapies against diseases like leishmaniasis.