Selection of Promising Novel Fragment Sized S. aureus SrtA Noncovalent Inhibitors Based on QSAR and Docking Modeling Studies

Abstract

Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent S. aureus SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used. The known SrtA inhibitors from the ChEMBL database with diverse scaffolds were first employed to derive descriptors and interpret their significance and correlation to activity. Then, the classification and regression QSAR models were built, which were used for rough ranking of the virtual library of the synthetically feasible compounds containing the dedicated motif. Additionally, the virtual library compounds were docked into the “activated” model of SrtA (PDB:2KID). The consensus ranking of the virtual library resulted in the most promising structures, which will be subject to further synthesis and experimental testing in order to establish new fragment-like molecules for further development into antivirulent drugs.

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

“…Whereas the SrtA binding site dynamics is relatively well studied [ 6 , 7 , 28 ], a brief survey of molecular modeling efforts for non-covalently bound small molecules reveals quite different binding modes and interaction patterns, with notably few persistent directed interactions, such as hydrogen and halogen bonds and salt bridges. Therefore, we composed a list of structure validation criteria to consider when assessing the feasibility of the ligand–SrtA complex, taking into account its complicated nature: The same and opposite charged groups proximity; Location of hydrophobic parts/residues—in pockets or in the solute; Reasonable placement of N- and C-termini, assuming continuation of the polypeptide chain; Reasonable proximity of the catalytically broken bond of an oligopeptide to Cys184 (or its place in case of C184A mutant)—the bonds between T and G in LPxTG and between D and A in LPRDA; If the position of binding close to the catalytically relevant one is sought, the side chain of x in LPxTG should not be restricted by the protein surface; If possible, Arg197 should participate in hydrogen bonding with a ligand as hydrogen bond donor [ 9 , 30 ]. …”

“…The latter results in the binding site looking significantly different even in PDB structures, not to mention the possible behavior in solution. Since the above difficulties complicate the straight-forward SBDD approach, any source of experimental information should be used to reconstruct the requirements of the binding site to a ligand [ 9 ]. In particular, starting from a validated hit compound becomes even more valuable than it is in the regular drug discovery project.…”

“…Our long-term aim is to use our expertise gained in covalent [ 16 ] and non-covalent small molecule [ 9 , 17 ] SrtA inhibitor development to start a new project using LPRDA oligopeptide as a base and, first, reveal the key interaction patterns for the LPRDA–SrtA complex, and, second, by gradual modification, come to a more potent and more drug-like lead compound [ 18 ] using SBDD methods and subsequent experimental validation. In this work we make an effort to establish protocols pertinent to computer-aided SBDD for further rational modifications and development by starting from the molecular modeling section of the work by Wang et al [ 15 ].…”

Oligopeptide Sortase Inhibitor Modulates Staphylococcus aureus Cell Adhesion and Biofilm Formation

“…We recently demonstrated that incubation of the S. aureus ATCC 29213 (MSSA) strain with small-molecule compounds from our in-house collection attenuated subsequent bacterial adhesion to Vero cells, which was in contrast to untreated staphylococci [ 19 ]. Furthermore, we predicted the properties of SrtA inhibitors for the same compounds [ 20 ]. Establishing a correlation between the indicated research results would improve translation processes related to the development of antivirulence antimicrobials, which prompted the current study of the pentapeptide LPRDA as a reference compound with both antiadhesive and sortase-inhibiting properties.…”

“…Due to our interest in the development of novel antibacterials with antiadhesive mechanisms of action [ 19 ], we selected a reference compound with confirmed activity and further potential for development. We previously demonstrated antiadhesive activity in a dual-cell assay [ 19 ] and predicted the properties of SrtA inhibitors [ 20 ] for some compounds from our in-house collection. After analyzing the available body of data [ 12 , 13 , 14 , 15 , 16 , 17 ], we concluded that the oligopeptide LPRDA has certain advantages over other SrtA inhibitors, primarily owing to good solubility, in vivo activity, and being a starting point for peptidomimetic development with modified properties.…”