Identification of flavone and its derivatives as potential inhibitors of transcriptional regulator LasR of Pseudomonas aeruginosa using virtual screening

Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to “not kill, but disarm” the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using multiple docking programs for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro / in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.HighlightsVirtual screening using multiple docking programs for consensus predictions.Virtual screening reveal benzamides as potential inhibitors of LasR.Selected compounds bind to the same amino acids of LBD as the native autoinducer.Selected compounds meet the criteria necessary for their consideration as drugs.GRAPHICAL ABSTRACT1: N- (1,3-benzodioxol-5-ylmethyl) -4- (6,8-dimethyl-4-oxochromen-2-yl) benzamide docking with LBD of LasR, A — ligand conformation predicted by AutoDock, B - by rDock and C - by LeDock,D - binding of CID 108754330 with LBD of LasR predicted by rDock.2: Four types of P. aeruginosa quorum sensing signaling systems I. Las, II. Rhl, III. Pqs and IV. IQS.