Role of ring positioning and preferential occupation of ligand obtained through molecular dynamics simulation of peptidoglycan associated lipoprotein (Pal).

Peptidoglycan associated lipoprotein (Pal) of Burkholderia cepacia is a highly attractive target as it is essential and conserved across strains of the pathogen and involved significantly in pathogenesis and survival. Herein, we used this target in virtual screening of small drug molecules library with an objective to screen the most appropriate antagonist for (Pal) to block its biological function. Results yielded a pyrimidine with imidazole group of compound "(R)-2-(1-(2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-carbonyl) piperidin-3-yl)-5-methlimidazol-3-ium-1-ide" showing the highest affinity for the active pocket of the protein and posed as such that the pyrimidine-4-carbonyl and piperidin-3-yl ring of the molecule is docked deep inside the pocket keeping the (R)-2-(piperidin-3-yl)imidazole-3-ium-1-ide posed outside this cavity. Molecular dynamics (MD) simulations illustrated stable binding of the compound at the docked site throughout the course of 600 ns (ns) with no conformational changes observed in the receptor macromolecule. Higher conformational stability was inferred for the system with mean RMSD of 1.1 Å supported with residual flexibility with mean value of 0.7 Å. Radial distribution function (RDF) showed the profound involvement of Arg56, Asp20 and Asp54 from protein active pocket in hydrogen bonding at the beginning and towards the end of simulation. The binding energy MMPB/GBSA and WaterSwap analyses showed an earnest contract on the affinity of inhibitor in response to hotspot residues of the active pocket. The role of stable positioning of rings inside the cavity is established through simulation, while a relevant comparative analysis indicates the compound as biologically active and potent candidate for therapeutic applications.