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• W4320151608 abstract "Background: Metabolic syndrome is a consequence of excess fatty acid accumulation in the human body, causing metabolic disorders related to the role of the two acetyl-CoA carboxylase (ACC) isoforms, ACC1 and ACC2. Inheriting the results from our previous research about the effective model of human acetyl-CoA carboxylase inhibition by aromatic-structure inhibitors, this research explains the inhibition mechanism of the enzyme by studying the interaction direction, preferential binding sites of aromatic ligands on the isoforms and conformational changes of enzyme-ligand complexes in the body’s environmental conditions (temperature 37 degrees Celsius and water solvent). Methods: This research applies hard docking combined with molecular dynamics and virtual screening of 14 inhibitory ligand groups, which have 50% enzyme inhibitor (IC50) values determined by experiments, including bipiperidylcarboxamide derivatives, polyketides, aryloxyphenoxypropionate, cyclohexanedione, synthetic acyl-CoA fatty acid chains, acylsulfonamide derivatives, Taisho inhibitors, Sanofi-Aventis inhibitors, AstraZeneca inhibitors, Takeda inhibitors, Pfizer inhibitors, Nimbus inhibitors, Amgen inhibitors and Boehringer Ingel-heim inhibitors. The geometric structures of the ligands are modeled and optimized by quantum mechanical methods, including PM3 for ACC1 and DFT at the B3LYP/6-31G(d,p) level for ACC2 based on our previous research about the QSAR enzyme-inhibition models, using Gaussian 09 W software. Results: Binding energy values at the identified preferential binding sites of aromatic ligands are closely correlated with the experimental log(IC50), which has statistical significance (p < 0.05): R2ACC1 = 96.3% and R2ACC2 = 78.9%. Those sites reveal the five reaction niches on ACC1, involving the two preferential binding regions in the order of amino acids 152 to 643 and 1632 to 2100, and the four reaction niches on ACC2, involving the two preferential binding regions in the order of amino acids 270 to 704 and 1831 to 2299. The molecular dynamic simulation of enzyme-ligand complexes in the body’s environmental conditions confirms that if ligands have fewer stereogenic interactions and are ready to form four types of bonds, including hydrogen, pi-alkyl, pi-cation and alkyl-alkyl bonds, their inhibitory activity will be higher. Conclusion: The research clarifies the inhibition mechanism of the enzyme in which ligands prefer to interact with amino acids 152 to 643 and 270 to 704 on the biotin carboxylase domain of ACC and amino acids 1632 to 2100 and 1831 to 2299 on the carboxyl transferase domain of ACC. In addition, the fewer stereogenic interactions of ligands and the easier it is to form four types of bonds, including hydrogen, pi-alkyl, pi-cation and alkyl-alkyl bonds, the higher their inhibitory activity." @default.
• W4320151608 created "2023-02-13" @default.
• W4320151608 date "2022-01-01" @default.
• W4320151608 modified "2023-09-30" @default.
• W4320151608 title "Studying the inhibition mechanism of human acetyl-CoA carboxylase by aromatic ligands in the treatment of fatty acid metabolic syndrome using computational chemistry methods" @default.
• W4320151608 doi "https://doi.org/10.32508/stdj.v25i4.4000" @default.
• W4320151608 hasPublicationYear "2022" @default.
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