In silico Analysis of Natural Iridoids as Primary Amoebic Meningoencephalitis Inhibitors: Molecular Docking, MD Simulation, MMPBSA, and DFT Analyses

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Iridoids have demonstrated various activities, including anti-inflammatory, anticancer, cardioprotective, antiviral, hepatoprotective, antihyperglycemic, and antiparasitic effects. The brain-eating amoeba Naegleria fowleri is responsible for primary amoebic meningoencephalitis, a brain inflammation. In this study, 52 iridoids were selected through an extensive literature survey, and 22 of these iridoids passed the drug-likeness filter. The selected iridoids were molecularly docked against the N. fowleri CYP51 receptor, using voriconazole as a standard for comparison. The docking score for voriconazole was -7.6 kcal/mol, while the scores for 10-isovaleroyl-dihydropenstemide and Patrinalloside A were -8.9 and -8.6 kcal/mol, respectively. According to molecular dynamics (MD) simulation data, the interacting amino acid residues exhibited fluctuations within a specific range, with the Root Mean Square Deviation (RMSD) values stabilizing throughout the experiment. When interacting with the receptor linked to amoebic meningoencephalitis, 10-isovaleroyl-dihydropenstemide and Patrinalloside A showed free binding energies of -71.922 kJ/mol and -61.243 kJ/mol, respectively, based on Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculations. Furthermore, Fragment Molecular Orbital (FMO) and Molecular Electrostatic Potential (MEP) analyses of 10-isovaleroyl-dihydropenstemide and Patrinalloside A revealed potential nucleophilic-electrophilic attack zones, indicating they are chemically reactive. The analysis of both compounds' ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicated non-toxic behaviour. These findings suggest that natural iridoids have significant potential in combating primary amoebic meningoencephalitis.