Pharmacophore based virtual screening for identification of marine bioactive compounds as inhibitors against macrophage infectivity potentiator (Mip) protein of Chlamydia trachomatis

Abstract

Macrophage infectivity potentiator (Mip) is the virulence factor from Chlamydia trachomatis that is primarily responsible for causing sexually transmitted diseases (STDs) and blindness. Mip possesses peptidyl-prolyl-cis/trans-isomerase (PPIase) activity that can be inhibited by FK506 or rapamycin. Substitution at the aspartate-142 position by leucine-142 and replacement at the tyrosine-185 position by alanine-185 in the catalytic site strongly reduces the PPIase activity of Mip proteins as reported earlier. There are no experimentally determined structures available for Chlamydia trachomatis Mip and the number of reported cases of blindness and STDs are increasing. Due to these facts, it is very important to design new inhibitors against Mip. So, we have modeled the protein structure by homology modeling. Further, a pharmacophore model and molecular docking simulations were employed to discover Mip inhibitors from a Universal Natural Product Database (UNPD) of 229 358 natural compounds. The docking experiment revealed two potential lead compounds, from which granaticin from Streptomyces violaceoruber and Plumarella from Marine coral species emerged as the top candidates. In addition, molecular dynamics (MD) simulations were carried out to analyze the conformational changes behind the molecular mechanism of Mip (native and mutants) for the screened novel lead compounds.