Theoretical Studies of Leu-Pro-Arg-Asp-Ala Pentapeptide (LPRDA) Binding to Sortase A of Staphylococcus aureus

Abstract

Sortase A (SrtA) of Staphylococcus aureus is a well-defined molecular target to combat the virulence of these clinically important bacteria. However up to now no efficient drugs or even clinical candidates are known, hence the search for such drugs is still relevant and necessary. SrtA is a complex target, so many straight-forward techniques for modeling using the structure-based drug design (SBDD) fail to produce the results they used to bring for other, simpler, targets. In this work we conduct theoretical studies of the binding/activity of Leu-Pro-Arg-Asp-Ala (LPRDA) polypeptide, which was recently shown to possess antivirulence activity against S. aureus. Our investigation was aimed at establishing a framework for the estimation of the key interactions and subsequent modification of LPRDA, targeted at non-peptide molecules, with better drug-like properties than the original polypeptide. Firstly, the available PDB structures are critically analyzed and the criteria to evaluate the quality of the ligand–SrtA complex geometry are proposed. Secondly, the docking protocol was investigated to establish its applicability to the LPRDA–SrtA complex prediction. Thirdly, the molecular dynamics studies were carried out to refine the geometries and estimate the stability of the complexes, predicted by docking. The main finding is that the previously reported partially chaotic movement of the β6/β7 and β7/β8 loops of SrtA (being the intrinsically disordered parts related to the SrtA binding site) is exaggerated when SrtA is complexed with LPRDA, which in turn reveals all the signs of the flexible and structurally disordered molecule. As a result, a wealth of plausible LPRDA–SrtA complex conformations are hard to distinguish using simple modeling means, such as docking. The use of more elaborate modeling approaches may help to model the system reliably but at the cost of computational efficiency.

Substrate-derived Sortase A inhibitors: targeting an essential virulence factor of Gram-positive pathogenic bacteria

“…With respect to our anticipated docking study the highly flexible binding pocket of SrtA is especially problematic, which has been shown by others and also agrees with our own experience from other computational studies. 42,46,47 The conformational flexibility of the substrate binding pocket was already observable in our short refinement simulation (Fig. S41†), showing that the β6/β7 loop quickly moves from the closed conformation in towards the open conformation, although a substrate mimicking peptide was present.…”

Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

“…We also showed that both prokaryotic and eukaryotic cell lines were viable under LPRDA influence and demonstrated LPRDA’s biofilm inhibitory properties. Our recent studies have revealed novel features in ligand–host interactions between LPRDA and S. aureus SrtA [ 21 ], which, in combination with the results of this study, could create a platform for more sophisticated antibacterial development. Most studies related to SrtA inhibitors and CWA proteins have been confined to a few laboratory strains.…”

“…Moreover, the authors mentioned in the experimental section that “to improve its pharmacokinetics and therapeutic efficacy, the oligopeptide was modified by PEG2000 modification and amide modification at the N- and C-termini, respectively” [ 18 ]. There were also inconsistencies in the molecular modeling of interactions of the pentapeptide LPRDA with the S. aureus SrtA active site, which prompted us to perform our own in-depth theoretical analysis [ 21 ].…”

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment

“…Further in silico studies were done by Shulga et al . on the LPRDA peptide binding activity and key interactions to SrtA of S. aureus [103] . The results showed different binding modes with two orientations in the binding site either in reversed polypeptide sequence orientation or direct sequence order of LPRDA.…”