Enhanced Antibacterial Activity of Novel Fluorescent Glutathione-Capped Ag Nanoclusters.

Ag nanomaterials are promising candidates for the discovery of next-generation antibiotics with a high antibacterial effect against multi-drug resistant strains. This paper reports a simple synthesis of novel water-soluble glutathione-capped silver nanoclusters (GSH-Ag NCs) with an enhanced antibacterial activity. According to thin layer chromatography (TLC), the synthesized GSH-Ag NCs are an individual fraction of the same composition without any impurities. According to matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and energy dispersive X-ray (EDX) analyses, the silver core of the GSH-Ag NCs contains approximately 35 silver atoms, and the molecular weight of these nanoclusters is about 11 kDa. The fabricated silver nanoclusters have a reddish fluorescence (λex/λem = 509/645 nm), with a large Stokes shift (>130 nm), and ultra-small size (less than 2 nm) according to transmission electron microscopy (TEM) data and dynamic light scattering (DLS) analysis. The antibacterial activity and minimal inhibitory concentrations of the silver nanoclusters towards Escherichia coli, Staphylococcus aureus, Bacillus cereus and Enterobacter cloacae were evaluated using the agar well-diffusion method and resazurin metabolism assay. The antibacterial activity of chelated silver in the nanoclusters was found to be significantly higher compared to the activity of free silver ions. To explain the possible mechanisms underlying the antibacterial actions of the GSH-Ag nanoclusters, molecular docking was performed, and prospective bacterial targets were identified using AutoDock.

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations.

The main (Mpro) and papain-like (PLpro) proteases are highly conserved viral proteins essential for replication of the COVID-19 virus, SARS-COV-2. Therefore, a logical plan for producing new drugs against this pathogen is to discover inhibitors of these enzymes. Accordingly, the goal of the present work was to devise a computational approach to design, characterize, and select compounds predicted to be potent dual inhibitors - effective against both Mpro and PLpro. The first step employed LigDream, an artificial neural network, to create a virtual ligand library. Ligands with computed ADMET profiles indicating drug-like properties and low mammalian toxicity were selected for further study. Initial docking of these ligands into the active sites of Mpro and PLpro was done with GOLD, and the highest-scoring ligands were redocked with AutoDock Vina to determine binding free energies (ΔG). Compounds 89-00, 89-07, 89-32, and 89-38 exhibited favorable ΔG values for Mpro (-7.6 to -8.7 kcal/mol) and PLpro (-9.1 to -9.7 kcal/mol). Global docking of selected compounds with the Mpro dimer identified prospective allosteric inhibitors 89-00, 89-27, and 89-40 (ΔG -8.2 to -8.9 kcal/mol). Molecular dynamics simulations performed on Mpro and PLpro active site complexes with the four top-scoring ligands from Vina demonstrated that the most stable complexes were formed with compounds 89-32 and 89-38. Overall, the present computational strategy generated new compounds with predicted drug-like characteristics, low mammalian toxicity, and high inhibitory potencies against both target proteases to form stable complexes. Further preclinical studies will be required to validate the in silico findings before the lead compounds could be considered for clinical trials.

Multistep rational molecular design and combined docking for discovery of novel classes of inhibitors of SARS-CoV-2 main protease 3CLpro.

The main protease (3CLpro) of SARS-CoV and SARS-CoV-2 is a promising target for discovery of novel antiviral agents. In this paper, new possible inhibitors of 3CLpro with high predicted binding affinity were detected through multistep computer-aided molecular design and bioisosteric replacements. For discovery of prospective 3CLpro binders several virtual ligand libraries were created and combined docking was performed. Moreover, the molecular dynamics simulation was applied for evaluation of protein-ligand complexes stability. Besides, important molecular properties and ADMET pharmacokinetic profiles of possible 3CLpro inhibitors were assessed by in silico prediction.

Docking and antibacterial activity of novel nontoxic 5-arylidenepyrimidine-triones as inhibitors of NDM-1 and MetAP-1.

Background: Antibiotic resistance, which occurs through the action of metallo-ß-lactamases (NDM-1), is a serious problem in the treatment of infectious diseases. Therefore, the discovery of new NDM-1 inhibitors and promising antibacterial agents as inhibitors of alternative targets (MetAP-1) is important. Method & results: In this study, a virtual library of 5-arylidene barbituric acids was created and molecular docking was performed for identification of novel possible inhibitors of NDM-1 and MetAP-1. Antibacterial activity (agar well-diffusion assay) and cytotoxicity (alamarBlue assay) of perspective compounds were evaluated. Pharmacokinetic profiles and molecular properties were predicted. Conclusion: We have identified possible novel inhibitors of NDM-1 and MetAP-1 with bacteriostatic activity, most of which are not cytotoxic and have potential excellent drug-likeness properties.