In Silico Identification of Novel High-Affinity Inhibitors of Naegleria fowleri CYP51

Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), a disease with a mortality rate exceeding 97%. Current therapeutic options are limited and often exhibit high toxicity. This study focuses on Sterol 14α-demethylase (CYP51), a critical enzyme for ergosterol biosynthesis, as a target. Using in silico molecular docking, we identified a novel inhibitor, designated as NOV-23, with an exceptional binding affinity of-11.9 kcal/mol. Pharmacokinetic profiling via Swis-sADME predicts favorable properties for CNS treatment: the candidate exhibits high Blood-Brain Barrier (BBB) permeation and high Gastrointestinal (GI) absorption. Key physicochemical parameters include a TPSA of 58.56 Å2 and a consensus LogP of 3.20. However, a Synthetic Accessibility score of 6.78 suggests structural complexity, indicating that while NOV-23 is a potent theoretical binder, future work should focus on scaffold simplification to facilitate chemical synthesis.