Computational Profiling of Asteraceae‐Derived Phytochemicals Targeting S‐Adenosylhomocysteine Hydrolase (SAHH) of <i>Naegleria fowleri</i>

Abstract Primary amoebic meningoencephalitis (PAM) is a rare but fatal disease caused by Naegleria fowleri ( N. fowleri ). This parasitic amoeba has adverse and deadly effects on humans and animals, as it thrives in fresh and warm water environments and has a mortality rate of up to 95%. The pathogen's resistance to current pharmacological regimens, even in combination drug therapies, is a major contribution to its high mortality. The current study aimed to investigate the potential of antiparasitic plants of the Asteraceae family for inhibiting N. fowleri's S‐adenosyl‐homocysteine hydrolase enzyme (Nf‐SAHH). An in‐house library of 716 natural products was obtained from selected ayurvedic antiparasitic plants and virtually screened against Nf‐SAHH. The identified hits were subjected to initial evaluation based on standard drug‐likeness criteria and ligand efficiency. Stability between the interacting residues of the target receptor and the top active ligands was further confirmed by molecular dynamic simulation. Our six top‐screened hits, namely, 3‐hexadecyloxy carbonyl‐5‐(2‐hydroxyethyl)‐4‐methyl imidazolium ion (HCEMI), geranylgeraniol (GGOH), hexadecanoic acid, 2‐hydroxy‐1‐(hydroxymethyl) ethyl ester, (+)‐sesamin (+)‐arborone, and octadecanoic acid 2,3‐dihydroxypropyl ester showed docking score greater than adenosine analogue (Neplanocin A). These inhibitors also adhered to established drug‐likeness criteria, demonstrating favorable ligand efficiency, pharmacophoric and pharmacokinetic properties. They exhibited stable results in molecular dynamics simulations with a broad spectrum of biological activities. Moreover, the concentration–time profile of HCEMI and geranylgeraniol indicated significant concentrations of these metabolites in the brain tissue to bind and inhibit Nf‐SAHH. Their activities extended beyond their robust affinity for the target protein. Predominantly non‐mutagenic, most of the hits possess the capability to permeate the blood–brain barrier (BBB). They inhibit the P‐glycoprotein, making them viable candidates for treating PAM infection. Given their potential to effectively inhibit the Nf‐SAHH protein, these hits warrant further investigation through in vitro and in vivo studies for the development of novel drugs against the PAM infection.