Peptidoglycan-associated lipoprotein (Pal) is a conserved protein in Gram-negative bacteria, attached to the inner leaflet of the outer membrane by means of an N-terminal lipid anchor. Pal alternately interacts with either peptidoglycan (PG) or with TolB, as part of the Pal-Tol complex. Pal and the Tol proteins play an integral role in stabilizing the bacterial membrane and facilitating the formation of the septum during cell division. While Pal is not strictly required for bacterial viability, it has been shown to contribute to the pathogenicity of various Gram-negative pathogens such as Escherichia coli (E. coli). As such, Pal may be an advantageous and effective target to combat pathogenesis. Structural and mutagenesis studies have demonstrated that Pal binds to both PG and TolB binding partner at an overlapping site – a putative binding “hotspot”. In order to characterize this putative hotspot on Pal, we employed virtual screening of numerous small molecules from the ZINC15 database using Dock6. Control experiments, rigid- and flexible-docking results, and results from virtual mutagenesis experiments will be discussed. The characterization of Pal’s molecular interactions is an important first step towards the development of therapeutics against Pal from Gram-negative bacterial pathogens.

Virtual screening of a putative binding hotspot in peptidoglycan associated lipoprotein from Burkholderia pseudomallei

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