Discovery of Marine Sponge Compound as Promising Inhibitor for Macrophage Infectivity Potentiator (Mip) Protein against Chlamydia pneumoniae

Abstract

Abstract:The macrophage infectivity potentiator (Mip) from Chlamydia pneumoniae is a major virulence factor. Mip is necessary for optimal intracellular infection and survival within both amoeba and human macrophages. Legionella and Chlamydia is the causative agent responsible for Legionnaires' disease, Blindness, Sexual Transmitted Disease (STD) and Pneumonia respectively. Mip exhibits peptidyl-prolyl-cis/trans-isomerase (PPIase) activity that is blocked by the immunosuppressant FK506 or rapamycin, the recent significant increase in the number of reported cases of Blindness, STD and Pneumonia. It is necessary to design of new inhibitors directed against Mip proteins of intracellular pathogens. The aim of this study was to construct the 3D model of Chlamydia pneumoniae Mip by homology modeling. Further, pharmacophore model design and molecular docking simulations were carried out to identify Mip inhibitors from a Universal Natural Product Database (UNPD) of over 229358 natural compounds. The virtual screening furnished 2 hit compounds, from which phorbaside C from Marine sponge Phorbas species and emerged as a top candidate. Along with molecular dynamics (MD) simulations which will be carried out to analyze the binding affinity for the screened novel, lead compounds. Lead compounds will be tested for their ability to inhibit the PPIase activity of Mip proteins in vitro and in vivo.

Exploring Chemical Diversity of Phorbas Sponges as a Source of Novel Lead Compounds in Drug Discovery

“…The stereo structure was established by comparison with other similar skeletons having the same cyclohexenone substructure. Phorbasin C (89) was spectroscopically very similar to phorbasin B (88). The molecular formula for phorbasin C (89) differed from phorbasin B (88) by 42 mass units (acetyl unit), and the 1 H NMR spectrum of phorbasin C (89) revealed signals related to the presence of a characteristic methyl acetate group.…”

“…A dereplication work through LCMS showed the presence of these phorbasins G-I in the extract of P. amaranthus [73]. Phorbasins E-F (91-92) are actually dimers, probably derived from phorbasin B or C (88)(89), fused by a seven-membered heterocyclic ring which incorporates a taurinyl residue, an unprecedented feature in natural product skeletons [70]. Analysis of the structures that form the dimers suggested that they may have the same biosynthetic origin and, therefore, a common absolute stereochemistry.…”

“…Phorbasin I (98) has an ethoxy group at C17, and phorbasin J (99) bears two ethoxy groups, respectively at C2 and C17, and so both phorbasins can be regarded as ethoxy derivatives of phorbasin H (97). Phorbasin K (100) was reported as the dihydro analogue of phorbasin B (88). Phorbasins I and J (98-99) are likely solvolysis artifacts generated by storage in ethanol.…”

“…Growth experiments suggested that this compound does not inhibit yeast cell growth but inhibits filamentous growth in C. albicans, which means that the phorbasin H (94) induces a change in C. albicans morphology [86]. Another study reported the ethanolic extract rich in phorbasins (87)(88)(89) from the Phorbas sp. could exert growth inhibitory activity against gram positive bacteria, such as Staphylococcus aureus and Micrococcus luteus.…”

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

“…Also mutation of the Legionella pneumophila Mip protein on catalytic residues at the aspartate-142 position replaced by leucine-142 and the tyrosine-185 position replaced by alanine-185 strongly reduces PPIase activity. 13 In order to design a drug for treating chlamydial infections, we constructed an in silico mutagenesis 14,15 model for both important catalytic residues (aspartate-170 to leucine-170 and tyrosine-213 to alanine-213) of C. trachomatis Mip, 16 validated the stability of the mutated model. The Universal Natural Products Database (UNPD) 17 was created to be a comprehensive resource of natural products for virtual screening.…”