New benzimidazole derivatives targeting LasR with antibiofilm efficacy against Pseudomonas aeruginosa: An integrated in vitro and molecular dynamics simulation- based investigation.

Abstract

In a continuation of our previous work, twenty benzimidazole derivatives were designed and synthesized as potential LasR antagonists based on extensive in silico and molecular dynamics simulation (MDS) experiments. Among all derivatives, three compounds, 6a, 7b and 8b showed a promising inhibition of biofilm formation, pyocyanin production, and rhamnolipids production of (52.4%, 53.8%, 37.1%), (59.4%, 64.7%, 51.6%), and (56.1%, 57.1%, 41%), respectively. Moreover, the modeled structures of these compounds were able to interact perfectly with LasR ligand binding pocket inducing complete dissociation of the protein's dimeric form over ∼ 400 ns MDS confirming their action as LasR antagonists. On the other hand, compounds 5a, 5c, 5e, 6c, 7a, 7d and 7e induced biofilm formation, pyocyanin production, and rhamnolipids production. These findings provide a functional model for LasR, which could aid in the future design of potent LasR modulators.