MM/GB(PB)SA integrated with molecular docking and ADMET approach to inhibit the fat-mass-and-obesity-associated protein using bioactive compounds derived from food plants used in traditional Chinese medicine

• Published in: Pharmacological research. Modern Chinese medicine Vol. 11; p. 100435
• Main Authors: Mandal, Manisha, Mandal, Shyamapada
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-06-2024; Elsevier
• Subjects: ADMET property; FTO; MM/GB(PB)SA free energy; Molecular docking; Obesity; Phytochemicals; FTO; MM/GB(PB)SA free energy; Obesity; ADMET property; Phytochemicals; Molecular docking
• ISSN: 2667-1425; 2667-1425
• DOI: 10.1016/j.prmcm.2024.100435

•FTO was used as druggable target and meclofenamic acid (MCFA) as reference drug.•Phytochemicals had higher affinity to FTO than MCFA by molecular docking.•MDS-based MM/GB(PB)SA proved energetically stable FTO-curcumin complex formation.•ADMET properties of phytochemicals were comparable with that of MCFA.•Curcumin was the compound of choice for FTO-associated obesity therapy.
Obesity is currently a major global concern, requiring the development of effective therapeutics. This study determines the inhibitory activity against FTO (fat mass and obesity-associated protein) of food plant-derived bioactive compounds of TCM (traditional Chinese medicine) importance, by in silico approaches.
Food plant-derived phytochemicals, such as curcumin (CCMN), cajaisoflavone (CJIF), cyanidin-3-O-glucoside (C3OG) and pelargonidin-3-glucoside (P3GS), were selected as ligands, and docked to FTO. The reference FTO-inhibitor used was meclofenmic acid (MCFA). MDS (molecular dynamic simulations) was accomplished with 10 ns run for the docked complex of FTO with the most potential phytocompound. The phytochemicals were subjected to bioactivity scoring, Lipinski's rule of five screening, and ADMET prediction. Law
Molecular docking demonstrated binding energies of -9.4, -8.8, -8.7 and -8.2 kcal/mol for CCMN, CJIF, C3OG and P3GS, respectively. The reference inhibitor MCFA had binding energy of -7.8 kcal/mol, and therefore, the FTO inhibition capacity of the ligands were in order of CCMN > C3OG > P3GS > CJIF > MCFA. The FTO residues His231, Ser229, Val228, Leu109, Tyr108 and Pro93 played crucial role in protein-ligands interaction displaying hydrogen bonds and hydrophobic contacts. MDS-based MM/GB(PB)SA binding free energies authenticated CCMN (-6.67/-8.77 kcal/mol) as a stronger FTO inhibitor than MCFA (0.19/-0.02 kcal/mol). Pharmacological properties of the phytochemicals predicted were comparable to MCFA standard.
TCM compounds of botanical origin are important for the effective management of obesity. In the current study, all the phytochemicals, the potential TCM ingredients, with acceptable pharmacological properties displayed excellent binding affinity and stronger inhibitory activity against FTO, compared to MCFA. FTO_CCMN displayed more energetic stability compared to FTO_MCFA using MM/GB(PB)SA approaches. Overall, this study paved the basis of FTO-associated obesity management with food plant-based therapeutics of TCM importance in the globe.
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