Computational approach for drug discovery against Gardnerella vaginalis in quest for safer and effective treatments for bacterial vaginosis.

Bacterial vaginosis (BV), primarily attributed to Gardnerella vaginalis, poses significant challenges due to antibiotic resistance and suboptimal treatment outcomes. This study presents an integrated approach to identify potential drug targets and screen compounds against this bacterium by leveraging a computational methodology. Subtractive proteomics of the reference strain ASM286196v1/UMB0386 (assembly accession: GCA_002861965.1) facilitated the prioritization of proteins with essential bacterial functions and pathways as potential drug targets. We selected 3-deoxy-7-phosphoheptulonate synthase (aroG gene product; also known as DAHP synthase) for downstream analysis. Molecular docking was employed in PyRx (AutoDock Vina) to predict binding affinities between aroG inhibitors from the ZINC database and 3-deoxy-7-phosphoheptulonate synthase. Molecular dynamics simulations of 100 ns, using GROMACS, validated the stability of drug-target interactions. Additionally, ADMET profiling aided in the selection of compounds with favorable pharmacokinetic properties and safety profile for human hosts. PBPK profiling showed that ZINC98088375 had the highest bioavailability and efficient systemic circulation. Conversely, ZINC5113880 demonstrated the lowest absorption rate (39.661%). Moreover, cirrhosis, steatosis, and renal impairment appeared to influence blood concentration of the drug, impacting bioavailability. The integrative -omics approach utilized in this study underscores the potential of computer-aided drug design and offers a rational strategy for targeted inhibitor discovery against G. vaginalis. The strategy is an attempt to address the limitations of current BV treatments, including antibiotic resistance, and pave way for the development of safer and more effective therapeutics.