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Background: Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile mechanisms of action. background: Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis situation. There is a need to develop anti-tuberculosis drugs with novel structures that have new mechanisms of action. Objective: In this study, we identified antimicrobial compounds with a novel skeleton that inhibits mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1). objective: This study aimed to identify antimicrobial compounds with a novel skeleton that inhibits mycobacterium Decaprenylphosphoryl-β-D-ribose oxidase (DprE1). Methods: A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and ompound 4. Results: Eight compounds were selected through in silico screening. Compound 4 showed strong growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and stable binding of Compound 4 to the active site of DprE1. method: A multi-step in silico structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. The growth inhibitory effect of the eight selected candidate compounds on Mycobacterium smegmatis was experimentally verified. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and Compound 4. Conclusion: The structural analysis of the novel scaffold in Compound 4 can pave way for anti-tuberculosis drug development and discovery. other: NA

The emergence of drug-resistant Staphylococcus aureus strains, such as methicillin-resistant S. aureus and vancomycinresistant S. aureus, and their spread not only inside hospitals but also outside hospitals has become a major problem worldwide. In this study, we investigated novel antimicrobial compounds targeting trimethoprim-resistant S. aureus dihydrofolate reductase (TMP-resistant saDHFR). A novel screening method, called the parallel compound screening (PCS) method, was established to analyze a common population of compounds that showed top scores using two docking tools, GOLD and AutoDock Vina. Using 154,118 compounds in the structural library, we conducted a threestep in silico structure-based drug screening, including PCS, and identified nine candidate compounds targeting TMP-resistant saDHFR. The growth inhibitory effects of the candidate compounds on bacteria were examined on Staphylococcus epidermidis, a model microbial strain of S. aureus. Among the candidate compounds, two compounds showed strong growth inhibition against S. epidermidis. The IC 50 values of the two compounds (6.34 and 56.94 µM) were determined. Molecular dynamics simulations predicted the direct and stable interactions between the active compounds and TMP-resistant saDHFR. The data regarding these active compounds from this study are expected to contribute to the development of new antibacterial agents against drug-resistant strains of S. aureus.

Background: Drug-resistant Staphylococcus aureus (S. aureus) has spread from nosocomial to community-acquired infections. Novel antimicrobial drugs that are effective against resistant strains should be developed.　S. aureus tyrosyl-tRNA synthetase (saTyrRS) is considered essential for bacterial survival and is an attractive target for drug screening. Objective: The purpose of this study was to identify potential new inhibitors of saTyrRS by screening compounds in silico and evaluating them using molecular dynamics (MD) simulations. Methods: A 3D structural library of 154,118 compounds was screened using the DOCK and GOLD docking simulations and short-time MD simulations. The selected compounds were subjected to MD simulations of a 75-ns time frame using GROMACS. Results: Thirty compounds were selected by hierarchical docking simulations. The binding of these compounds to saTyrRS was assessed by short-time MD simulations. Two compounds with an average value of less than 0.15 nm for the ligand RMSD were ultimately selected. The long-time (75 ns) MD simulation results demonstrated that two novel compounds bound stably to saTyrRS in silico. Conclusion: Two novel potential saTyrRS inhibitors with different skeletons were identified by in silico drug screening using MD simulations. The in vitro validation of the inhibitory effect of these compounds on enzyme activity and their antibacterial effect on drug-resistant S. aureus would be useful for developing novel antibiotics.