Abstract
To find potential inhibitors of Naegleria fowleri S-adenosyl-L-homocysteine hydrolase (NfSAHH), a brain-eating parasite, structure-based drug design was adopted. N. fowlerica causes primary amebic meningoencephalitis (PAM), a fatal central nervous system (CNS) disorder if untreated. NfSAHH protein (PDB ID: 5v96), involved in parasite growth and gene regulation, was targeted and screened against 163 metabolites from Gossypium hirsutum (cotton plant). With the aid of different software and web tools, the metabolites were subjected to several analyses. The RMSD was evaluated to validate our molecular docking strategy. Neplanocin A, a common anti-parasitic medication, was used as a reference to select top ligands for post-docking studies. Significant interactions were observed with residues THR-198, HIS-395, and MET-400. The drug-likeness of the top fifty hits was analyzed using Lipinski, Ghose, Veber, Egan, and Muegge rules. The top ten compounds following Lipinski's RO5 were studied regarding medicinal chemistry, pharmacokinetic simulation, and Swiss target prediction. Advanced strategies, including molecular dynamic simulations, binding energy calculations, and principal component analysis, were employed for the top three hits, namely curcumin, heliocide H2, and piceid, which indicated that heliocide H2 is the most promising candidate, while curcumin and piceid may need further optimization to improve their stability. Overall, the top ten phytochemicals, dotriacontanol, melissic acid, curcumin, 6,6'-dimethoxygossypol, phytosphingosine 2, methyl stearate, stearic acid, piceid, heliocide H2, and 6-methoxygossypol, reported in our study, are worthy enough to be subjected to in vivo and in vitro experimentation to find a novel drug to treat PAM.