Computational Evaluation of Neem-Derived Compounds as FTO Inhibitors for Metabolic Disorder Therapy

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The study of fat mass and obesity-associated (FTO) enzymes holds promise for managing metabolic disorders and preventing cancer growth. Neem-derived compounds have shown potential as natural inhibitors of FTO. This study aimed to evaluate the effectiveness of neem-derived chemicals as FTO inhibitors by analyzing their electronic properties, drug-like characteristics, and molecular interactions. Molecular docking simulations were performed to assess the binding affinity of neem-derived compounds with FTO. Drug-likeness was evaluated using Lipinski’s rule of five, and electronic properties were analyzed using HOMO-LUMO energy gaps. Quercetin exhibited the strongest binding affinity (-7.80 kcal/mol) and the most thermodynamically stable binding free energy (-45.749 kcal/mol) due to stabilizing interactions with active site residues HIS320, ARG316, LEU203, and SER229. Nimbidol (-7.70 kcal/mol), Nimbidin (-7.50 kcal/mol), and Gedunin (-7.40 kcal/mol) also demonstrated inhibitory potential. Drug-likeness assessments showed that all compounds, except Azadirachtin, met pharmacokinetic suitability criteria. The significant HOMO-LUMO energy gap in quercetin indicated high molecular stability, reinforcing its potential as a promising drug-like molecule. Neem-derived compounds, especially quercetin, may act as FTO inhibitors and could be developed into plant-based treatments for metabolic disorders, though further biological testing is needed.