In-silico quest of machine learning enabled identification of potential inhibitors against MDR Achromobacter xylosoxidans

Abstract

Achromobacter xylosoxidans is a gram-negative bacterium that belongs to family Alcaligenaceae. It is primarily responsible for healthcare-associated infections i.e. chronic purulent otitis, meningitis, pneumonia, peritonitis, UTIs, chronic obstructive pulmonary disease, and other illnesses. It can occasionally cause high death rates (15–30%) that can reach >50%. Following the subtractive proteomics approach, ATPase GspE was selected as the target protein for this study. ATPase GspE is a part of the whole secretion machinery that make up the Type II Secretion System. It powers the entire secretion process by binding with ATP and hydrolyzing it. T2SS is increasingly recognized as a key driver of virulence in many pathogenic organisms. Since GspE governs the whole T2SS, therefore targeting it was thought to have a profound effect on the normal functioning of the whole T2SS. An extensive machine learning-enabled computational investigation was followed in the current study. Drug libraries were screened using machine learning random forest algorithm trained on non-redundant dataset of 8722 antibacterial compounds with reported IC50 values. Active compounds were then further subjected to molecular docking. Three-dimensional structure of the GspE ATPase protein was predicted using AlphaFold and validated. Subsequently, for comparative analysis the molecular docking of GspE against screened was performed using GOLD software. In-silico analysis i.e. MD Simulations, Atom Contacts, SASA, Hydrogen Bond , RDF, binding free energy calculations, PCA and AFD analysis were performed on the selected inhibitors. Findings from this Insilco framework suggested that Asinex-BAS00263070-28551 is emphasizing its inhibitory potency against the target by making hydrogen bond interactions with Walker A motif, suggesting it could serve as the promising drug candidate against GspE. Further experimental in-vivo and in-vitro validation is still required to authenticate the therapeutic effects of these drugs.