Ensemble Docking as a Tool for the Rational Design of Peptidomimetic Staphylococcus aureus Sortase A Inhibitors

Sortase A (SrtA) of <i>Staphylococcus aureus</i> has long been shown to be a relevant molecular target for antibacterial development. Moreover, the designed SrtA inhibitors act via the antivirulence mechanism, potentially causing less evolutional pressure and reduced antimicrobial resistance. However, no marketed drugs or even drug candidates have been reported until recently, despite numerous efforts in the field. SrtA has been shown to be a tough target for rational structure-based drug design (SBDD), which hampers the regular development of small-molecule inhibitors using the available arsenal of drug discovery tools. Recently, several oligopeptides resembling the sorting sequence LPxTG (Leu-Pro-Any-Thr-Gly) of the native substrates of SrtA were reported to be active in the micromolar range. Despite the good experimental design of those works, their molecular modeling parts are still not convincing enough to be used as a basis for a rational modification of peptidic inhibitors. In this work, we propose to use the ensemble docking approach, in which the relevant SrtA conformations are extracted from the molecular dynamics simulation of the LPRDA (Leu-Pro-Arg-Asp-Ala)-SrtA complex, to effectively represent the most significant and diverse target conformations. The developed protocol is shown to describe the known experimental data well and then is applied to a series of new peptidomimetic molecules resembling the active oligopeptide structures reported previously in order to prioritize structures from this work for further synthesis and activity testing. The proposed approach is compared to existing alternatives, and further directions for its development are outlined.