Virtual Screening for Potential Selective Inhibitors of Macrophage Infectivity Potentiator Proteins

Abstract

The bacterial Macrophage Infectivity Potentiators proteins (MIPs) appear to play a crucial role in bacterial penetration of epithelial linings and infection of macrophages. MIPs possess a binding domain analogous to human FK506 Binding Proteins (FKBP) that binds and weakens collagen membrane, allowing bacterial passage into tissues and away from the lysosomes of macrophages. Diverse strains of lethally infective bacteria, such as Legionella pneumophila (LP), Burkholderia pseudomallei and Coxiella burnetii, express MIPs or MIP-like proteins. We hypothesize that dosing MIP selective inhibitors could prevent bacterial infiltration of epithelial linings or macrophages while sparing human immune response. To identify prospective ligands, the key interactions of rapamycin bound to LP MIP were converted to pharmacophores and searched against all available chemicals in ZINCPharmer. After preparing the proteins and potential ligands in UCSF Chimera, ZINCPharmer hits were docked against the LP MIP and human FKBP12 using AutoDock 4. Multiple hits with affinity similar to rapamycin against LP MIP were identified, some of which are predicted to have lower affinities than rapamycin against FKBP12. These virtual screening hits represent potential starting points for potent, selective MIP inhibitors, providing possibly prophylactic measures or even treatments against drug resistant bacteria.