Data on molecular docking and molecular dynamics targeting Mycobacterium tuberculosis shikimic acid kinase.

We have previously performed a hierarchical in silico screening of a Mycobacterium tuberculosis shikimic acid kinase [1]. Specifically, 11 compounds were screened from a library of 154,118 compounds provided by ChemBridge [2] using UCSF DOCK [3] and the GOLD [4] program in the first and second steps, respectively. Molecular dynamic simulations were further performed on compound 2 (2-[(5Z)-5-(1-benzyl-5bromo-2-oxoindol-3-(5Z)-5-(1-benzyl-5-bromo-2-oxoindol-3-(5Z)-4-oxo-2 ylidene)-4oxo-2-sulfanylidene-1,3-thiazolidin-3-yl] acetic acid), which showed antimicrobial efficacy. These processes yielded ligand docking scores and trajectories. In this data article, we have added solvent-accessible surface area and PCA analyses, which were calculated from the raw docking scores and trajectories. Data obtained from molecular docking and molecular dynamic simulations are useful in two ways: (1) Further support for previous work (2) Provides a stepping stone for experimental scientists to conduct in silico studies and research ideas for other drug discovery researchers and computational biologists. We believe that this article will provide an opportunity to develop new Mycobacterium tuberculosis therapeutics through searching for analogs and inhibitors against new targets.

In silico Identification of Potential Inhibitors Against Staphylococcus Aureus Tyrosyl-tRNA Synthetase.

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.

Identification of novel antimicrobial compounds targeting Mycobacterium tuberculosis shikimate kinase using in silico hierarchical structure-based drug screening.

The development of new anti-TB drugs to prevent the spread of multidrug-resistant Mycobacterium tuberculosis (Mtb) strains is imperative. Mtb shikimate kinase (MtSK) was selected as the target protein to screen for new anti-TB drugs. We performed hierarchical in silico screening using a library of 154,118 compounds to search for novel compounds that could bind to the active site of MtSK. The growth-inhibitory effects of the candidate compounds on Mycobacterium smegmatis were evaluated in vitro. Nine of the 11 candidate compounds exhibited inhibitory effects against mycobacteria in vitro. The inhibitory activity of Compound 2 (IC50 = 1.39 µM) was higher than that of isoniazid, the first-line drug for TB treatment. Moreover, Compound 2 did not exhibit toxicity against mammalian cells and Escherichia coli. Molecular dynamics simulations using the MtSK-Compound 2 complex structure in a timeframe of 100 ns suggested that Compound 2 could stably bind to MtSK. The binding free energy of Compound 2 was estimated to be -37.96 kcal/mol using the MM/PBSA method, demonstrating that Compound 2 can stably bind to MtSK. These in silico and in vitro results indicated that Compound 2 is a promising hit compound for the development of novel anti-TB drugs.

Decrease in cholesterol in the cell membrane is essential for Nrf2 activation by quercetin.

Quercetin is a flavonoid with various cytoprotective effects. We previously reported that quercetin exerts anti-allergic, anti-oxidative, and anti-fibrotic activities via the induction of heme oxygenase (HO)-1. However, the mechanisms by which quercetin induces HO-1 to exhibit cytoprotective effects are poorly understood. We focused on its action on the cell membrane, which is the first part of the cell to interact with the extracellular environment. The cell membrane contains lipid rafts and caveolae, which play important roles in cellular signaling. A recent study showed that nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating anti-oxidative enzymes including HO-1, interacts with caveolin-1 (Cav-1), a component of caveolae, to regulate cellular anti-oxidative capacity. In this study, we investigated the changes in the cell membrane that leads to the induction of HO-1 by quercetin. Quercetin decreased the amount of cholesterol in the raft fractions, which in turn promoted the induction of HO-1. It also changed the composition of the lipid rafts and decreased and increased the expression of Cav-1 in the raft and non-raft fractions, respectively. Nrf2, which was localized in the cell membrane under resting conditions, was translocated along with Cav-1 to the nucleus after exposure to quercetin. These findings indicate for the first time that the HO-1-dependent cytoprotective effects of quercetin are mediated by the structural changes in lipid rafts brought about by decreasing the amount of cholesterol in the cell membrane, which thereby results in the translocation of the Cav-1-Nrf2 complex to the nucleus and induces the expression of HO-1.