Parasites & vectors · 2026
Cyclin-dependent kinase-inhibitor screening and structural analysis identify a CDK-like kinase candidate in Naegleria fowleri.
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Kim Min-Jeong, No Joo Hwan
Аннотация
BACKGROUND: Primary amebic meningoencephalitis (PAM) caused by Naegleria fowleri is a highly fatal central nervous system infection for which effective treatment options remain limited. This study explored CDK-related pathways in N. fowleri using a focused CDK inhibitor library and structure-based analysis of a selected CDK-like protein.
METHODS: A library of 126 CDK inhibitors was screened against N. fowleri trophozoites using a luminescence-based ATP viability assay, and active compounds were further evaluated in dose-response assays. Human CDK1-9 sequences were used for BLASTp searches against the N. fowleri proteome, followed by comparative sequence analysis with Trypanosoma brucei cdc2-related kinases (CRKs). Nf_CDK-like protein1 (FDP41_013684) was selected for homology modeling, molecular docking, and 100-ns molecular dynamics simulations.
RESULTS: Screening identified 23 active CDK inhibitors with IC50 values ≤ 10 μM against N. fowleri, including five prioritized compounds with submicromolar activity: AZD5438, GSK-3 inhibitor IX, milciclib, roniciclib, and SU9516 (IC50, 0.30-0.88 μM). Sequence analysis identified five CDK-like proteins in the N. fowleri proteome, among which Nf_CDK-like protein1 showed the highest similarity to T. brucei CRK3 and shared approximately 58-61% sequence identity with human CDK1/2. Conserved kinase features, including the glycine-rich loop, αC-helix, hinge region, DFG motif, and activation loop, were retained in Nf_CDK-like protein1. Docking analysis placed all five prioritized compounds within the predicted ATP-binding cleft, with shared interactions around Lys60, Tyr42, Asp113, and the hinge-proximal residues Ile110 and Asp111. Molecular dynamics simulations showed generally stable protein backbones and ligand poses over 100 ns.
CONCLUSIONS: This study identified multiple CDK inhibitor scaffolds with potent in vitro activity against N. fowleri and supports Nf_CDK-like protein1 as a plausible CDK-like kinase target candidate through integrated phenotypic and structure-based analyses, with direct biochemical validation needed in future studies. These findings suggest that CDK-like pathways may represent a relevant molecular axis in N. fowleri and provide a basis for future structure-guided optimization of anti-amoebic candidates.
METHODS: A library of 126 CDK inhibitors was screened against N. fowleri trophozoites using a luminescence-based ATP viability assay, and active compounds were further evaluated in dose-response assays. Human CDK1-9 sequences were used for BLASTp searches against the N. fowleri proteome, followed by comparative sequence analysis with Trypanosoma brucei cdc2-related kinases (CRKs). Nf_CDK-like protein1 (FDP41_013684) was selected for homology modeling, molecular docking, and 100-ns molecular dynamics simulations.
RESULTS: Screening identified 23 active CDK inhibitors with IC50 values ≤ 10 μM against N. fowleri, including five prioritized compounds with submicromolar activity: AZD5438, GSK-3 inhibitor IX, milciclib, roniciclib, and SU9516 (IC50, 0.30-0.88 μM). Sequence analysis identified five CDK-like proteins in the N. fowleri proteome, among which Nf_CDK-like protein1 showed the highest similarity to T. brucei CRK3 and shared approximately 58-61% sequence identity with human CDK1/2. Conserved kinase features, including the glycine-rich loop, αC-helix, hinge region, DFG motif, and activation loop, were retained in Nf_CDK-like protein1. Docking analysis placed all five prioritized compounds within the predicted ATP-binding cleft, with shared interactions around Lys60, Tyr42, Asp113, and the hinge-proximal residues Ile110 and Asp111. Molecular dynamics simulations showed generally stable protein backbones and ligand poses over 100 ns.
CONCLUSIONS: This study identified multiple CDK inhibitor scaffolds with potent in vitro activity against N. fowleri and supports Nf_CDK-like protein1 as a plausible CDK-like kinase target candidate through integrated phenotypic and structure-based analyses, with direct biochemical validation needed in future studies. These findings suggest that CDK-like pathways may represent a relevant molecular axis in N. fowleri and provide a basis for future structure-guided optimization of anti-amoebic candidates.