Structure based virtual screening and molecular dynamics of natural anti-biofilm compounds against SagS response regulator/sensor kinase in <i>Pseudomonas aeruginosa</i>

SagS sensor regulator plays a vital role in biofilm development of <i>Pseudomonas aeruginosa</i> which subsequently makes the cells more tolerant to various antimicrobials. The multidrug resistance (MDR) issue has risen substantially in recent years and is considered a global threat. Therefore, alternative compounds should be unearthed immediately to address the issues related to <i>P. aeruginosa</i> drug resistance for which SagS could be a candidate. The present study is an attempt to screen natural anti-biofilm compounds as the potent inhibitors of SagS. Twenty natural anti-biofilm/quorum sensing inhibiting compounds were retrieved from various literatures with significant inhibitory effects against <i>P. aeruginosa</i> biofilm from <i>in-vitro</i> experiments which were screened using various pharmacokinetic parameters. The screened and three standard drugs were docked against SagS-HisKA using AutoDock 4.2 tool, which were further analysed by MD simulations to understand the binding mode of compounds and dynamic behaviour of the complexes. Two potential anti-biofilm natural compounds, pinocembrin with binding affinity (-7.19 kcal/mol), vestitol (-7.18 kcal/mol) and the standard drug ceftazidime (-8.89 kcal/mol) were selected based on filtered parameters and better binding affinity. The trajectory analysis of MD simulations reflected Pinocembrin in stabilizing the system compared to ceftazidime. The existing reports state that the natural products represent promising source of therapy with least or almost nil adverse effect compared to synthetic drugs which is well collated with our <i>in-silico findings</i>. This investigation can save both time and cost required for <i>in-vitro</i> and <i>in-vivo</i> analysis for designing of a novel anti-biofilm agent against <i>P. aeruginosa</i> biofilm-associated infections. Communicated by Ramaswamy H. Sarma