Abstract 2485 Automated multiscale milestoning simulation pipeline integrating machine-learned force fields for accelerated drug-target kinetic predictions for accelerated drug discovery

Antibiotic resistance is a growing concern with multidrugresistant pathogens on the rise, and new antibiotics need to be discovered and developed to combat them.Bacteria continue to adapt and evolve to survive current therapies, thus reinforcing the need for new therapeutics that target novel bacterial targets.The sodium-dependent NADH:ubiquinone oxidoreductase (Na+-NQR) enzyme is a six-subunit respiratory complex found in a variety of pathogenic organisms including V. cholera and Pseudomonas Klebsiella and represents a novel and promising antibiotic target.The role of Na+-NQR in bacterial respiration is comparable to mitochondrial complex I, although the two enzyme complexes are quite distinct in structure, mechanism and phylogeny.Na+-NQR serves to provide energy for the bacterial cell and is involved in cell motility, secretion of toxins and other vital functions.Our lab aims to discover potent inhibitors of Na+-NQR to serve as potential new antibiotics.A targeted library of ubiquinone-like compounds was tested against Na+-NQR which resulted in the discovery of naphthoquinone lead molecules which are able to suppress the activity of the enzyme and promote bacterial cellular death.Progress in the synthesis and modulation of naphthoquinone Na+-NQR inhibitors will be reported.