We present adaptive resolution molecular dynamics simulations of aqueous and apolar solvents using coarse-grained molecular models that are compatible with the MARTINI force field. As representatives of both classes of solvents we have chosen liquid water and butane, respectively, at ambient temperature. The solvent molecules change their resolution back and forth between the atomistic and coarsegrained representations according to their positions in the system. The difficulties that arise from coupling to a coarsegrained model with a multimolecule mapping, for example, 4-to-1 mapping in the case of the Simple Point Charge (SPC) and MARTINI water models, could be successfully circumvented by using bundled water models. We demonstrate that the presented multiscale approach faithfully reproduces the structural and dynamical properties computed by reference fully atomistic molecular dynamics simulations. Our approach is general and can be used with any atomistic force field to be linked with the MARTINI force field.
COBISS.SI-ID: 5465114
Increasing bacterial resistance to available antibiotics stimulated the discovery of novel efficacious antibacterial agents. The biosynthesis of the bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of the UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. In our previous computational studies, the C-terminal domain motion of the MurD ligase was investigated using Targeted Molecular Dynamic (TMD) simulation and the Off-Path Simulation (OPS) technique. In this study, we present a drug design strategy using multiple protein structures for the identification of novel MurD ligase inhibitors. Our main focus was the ATPbinding site of the MurD enzyme. In the first stage, three MurD protein conformations were selected based on the obtained OPS/TMD data as the initial criterion. Subsequently, a two-stage virtual screening approach was utilized combining derived structure-based pharmacophores with molecular docking calculations. Selected compounds were then assayed in the established enzyme binding assays, and compound 3 from the aminothiazole class was discovered to act as a dual MurC/MurD inhibitor in the micomolar range. A steady-state kinetic study was performed on the MurD enzyme to provide further information about the mechanistic aspects of its inhibition. In the final stage, all used conformations of the MurD enzyme with compound 3 were simulated in classical molecular dynamics (MD) simulations providing atomistic insights of the experimental results. Overall, the study depicts several challenges that need to be addressed when trying to hit a flexible moving target such as the presently studied bacterial MurD enzyme and show the possibilities of how computational tools can be proficiently used at all stages of the drug discovery process.
COBISS.SI-ID: 5462810
The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands.
COBISS.SI-ID: 5514010