Interaction of gentamicin and gentamicin-AOT with poly-(lactide-co-glycolate) in a drug delivery system - density functional theory calculations and molecular dynamics simulation

Gentamicin is used to treat brucellosis, an infectious disease caused by the Brucella species but the drug faces several issues such as low efficacy, instability, low solubility, and toxicity. It also has a very short half-life, therefore, requiring frequent dosing. Consequently, several other antibiotics are also being used for the treatment of brucellosis as a single dose as well as in combination with other antibiotics but none of these therapies are satisfactory. Nanoparticles in particular polymer-based ones utilizing polymers that are biodegradable and biocompatible for instance PLGA are a method of choice to overcome such drug delivery issues and enable potential targeted delivery. The current study focuses on the evaluation of the structural and dynamical properties of a drug-polymer system consisting of gentamicin drug and PLGA polymer nanoparticles in the water representing a targeted drug delivery system for the treatment of brucellosis. For this purpose, all-atom molecular dynamics simulations were carried out on the drug-polymer systems in the absence and presence of the surfactant bis(2-Ethylhexyl) sulfosuccinate (AOT) to determine the structural and dynamical properties as well as the effect of the surfactant on these properties. We also investigated systems in which the polymer constituents were in the form of monomeric units toward decoupling the primary interactions of the monomer units and polymer effects. The simulation results explain the nature of the interactions between the drug and the polymer as well as transport properties in terms of drug diffusion coefficients, which characterize the molecular behavior of gentamicin-polymer nanoparticles for use in brucellosis

Understanding LuxS-based quorum sensing and its inhibition – molecular dynamics simulation study

<p>Molecular dynamics simulations were successfully applied to LuxS protein and its protein–ligand complex using the newly developed force field parameters for the iron containing active site. To the best of our knowledge, this was the first attempt to develop force field parameters for the iron containing active site of the LuxS protein. From the simulations, catalytically important amino acid residues were identified which were found to stabilise the ligand. Two residues Glu57 and Asp77 were involved in polar interactions while the protein region in the range between amino acid residue 125 and 131 were predicted to facilitate the entry of ligand to the active site. Other residues like Arg65, Asp77, Ile78 and Ser79 were also recognised as ligand stabilising factors deduced from the simulation. These results were also found to be in good agreement with earlier studies and thus demonstrated the successful application of MD simulations to the LuxS protein. Moreover, the simulation data were expected to be considered for the development of rational approaches in order to identify new LuxS-based quorum sensing antagonists for the treatment of pathologies caused by resistant bacteria.</p

Lead identification against <i>Mycobacterium tuberculosis</i> using highly enriched active molecules against pantothenate synthetase

The Pantothenate synthetase (PS) from the Mycobacterium tuberculosis (Mtb) holds a crucial role in the survival and robust proliferation of bacteria through its catalysis of coenzyme A and acyl carrier protein synthesis. The present study undertook the PS drug target in complex with a co-crystallized ligand and subjected it to docking and virtual screening approaches. The experimental design encompassed three discrete datasets: an active dataset featuring 136 compounds, an inactive dataset comprising 56 compounds, and a decoys dataset curated from the zinc library, comprising an extensive compilation of approximately 53,000 compounds. The compounds’ binding energies were observed to be in the range of −5 to ∼−14 kcal/mol. Additionally, binding energy results were further refined through Enrichment Factor analysis (EF). EF is a new statistical approach which uses the scores obtained from docking-based virtual screening and predicts the precision of the scoring function. Remarkably, the Enrichment Factor (EF) analysis produced exceptionally favorable outcomes, attaining an EF of approximately 49% within the uppermost 1% fraction of the compound distribution. Finally, a total of eight compounds, evenly distributed between the active dataset and the decoys dataset, emerged as potent inhibitors of the Pantothenate synthetase (PS) enzyme. The analysis of inhibition constants and binding energy revealed a notable correlation, with an r-squared value (r2) of 0.912 between the two parameters. Furthermore, the shortlisted compounds were subjected to 100 ns MD simulation to determine their stability and dynamics behavior. The decoy compounds that have been identified, exhibiting properties comparable to the active compounds, are postulated as potential candidates for targeting the Pantothenate synthetase (PS) enzyme to treat Mtb infection. Nevertheless, in the pursuit of a comprehensive investigation, it is advisable to undertake additional experimental validation as a component of the subsequent study. Communicated by Ramaswamy H. Sarma.</p