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From normal to competo-allosteric regulation: insights into the binding pattern dynamics of DSPI protein of Pseudomonas aeruginosa

Abstract DSPI, a putative enoyl-coenzyme A (CoA) hydratase/isomerase, is anticipated to be involved in the synthesis of cis-2-decenoic acid (CDA), a quorum sensing (QS) signal molecule present in the superbug Pseudomonas aeruginosa. The current study not only adapts a broad-spectrum strategy for the lucid design of small molecule modulators but also provides novel allosteric inhibitors for DSPI, to investigate its function and potential as a therapeutic target. Docking analysis revealed that the compound 10252273, bound to the specific allosteric site, interacted with Glu118, unique amino acid residue of the active binding pocket, hence indicates the presence of a competitive allosteric site. The current study thus identifies and characterizes inhibitors by targeting the normal binding site and also reports the presence of the competo-allosteric site in the same binding tunnel as the normal site. Molecular docking studies proposed two chemical compounds that share a benzamide-benzimidazole (BB) backbone as potent inhibitors that can obstruct the mechanism of DSPI by targeting both the normal and proposed allosteric binding sites. MD simulations further revealed the disruption of the normal binding site due to the displacement of critical residues Cys146 and Glu118. The rearrangement of H-bond pattern, pi-pi interactions, and strong hydrophobic interactions were observed at both the binding sites. The allosteric pocket inhibitor exhibited improved binding energy than the normal site inhibitor based on MMGBSA and MMPBSA analysis. With subsequent characterization, the current study reveals the allosteric binding site and provides insights into the drug binding mechanism of DSPI. Communicated by Ramaswamy H. Sarma