Computational Identification of N-PFP Inhibitors for Naegleria fowleri: Docking, DFT, and MD Approaches

Primary amoebic meningoencephalitis (PAM) is a deadly disease caused by the free-living pathogenic ameboflagellate Naegleria fowleri, which directly affects the central nervous system. There are only a handful of people throughout the world who have survived this deadly disease. Its alarmingly high mortality rate is due to a lack of a better understanding of the mode of action of the causative agent. Existing treatment options are available in the form of combinatorial drugs, but due to the blood-brain barrier (BBB), a small amount of active substance is reached at the target site. In this study, the membrane-bound, pore-forming protein (N-PFP) of N. fowleri was selected as an anti-pathogenic target. N-PFP, a novel protein of N. fowleri, was docked against several screened-out virtual compounds, based on ADMET criteria, from the Gold and platinum files of the ASINEX library, containing 261120 compounds. For docking analysis, 1-Methyl-4-{(E)-2-[6-methyl-2-(4-morpholinyl)-3-quinolinyl] vinyl} pyridinium was selected as a potential inhibitor. DFT analysis and MD simulations studies were performed, and the mentioned ligand was found to be of promising use for therapeutic purposes against N. fowleri. Further, in vivo and in vitro studies for this compound were recommended as a potential anti-pathogenic molecule.