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Description
Carnitine palmitoyltransferase 1A (CPT1A) is a mitochondrial enzyme essential for
transporting long chain fatty acids into mitochondria for β-oxidation by converting acyl
CoA to acylcarnitines. Its activity is regulated by malonyl CoA to prevent concurrent fatty
acid synthesis and degradation. CPT1A dysregulation is implicated in obesity, hypoketotic
hypoglycemia, neurodegenerative and cardiovascular diseases, diabetes, and cancer,
where many tumors rely on CPT1A mediated fatty acid oxidation for survival and drug
resistance. Although inhibitors such as etomoxir can block CPT1A, clinical use is limited
by toxicity. Hypoglycin A and B, naturally occurring toxins from unripe Blighia sapida
(ackee) fruit, and their derivatives, methylenecyclopropylacetic acid (MCPA) and
methylenecyclopropylacetic acid coenzyme A (MCPA-CoA) were investigated for CPT1A
inhibition using molecular docking and molecular dynamics simulations. Docking showed
MCPA-CoA had the strongest binding affinity (−8.0 to −7.3 kcal/mol). All compounds
interacted with key residues (His473, Tyr 602, Phe 712, Tyr 589 and Asp 477) at the
carnitine binding site. After 200 ns MD simulations, only carnitine, hypoglycin A, and
MCPA-CoA remained stable, with MCPA-CoA inducing significant changes in protein
backbone under dynamic conditions. MCPA left its initial site midway through the
simulation but still altered protein RMSD. These findings suggest hypoglycins and their
metabolites are potential CPT1A inhibitors, warranting derivatization into safer analogs
for therapeutic development.