Tecnologico de Monterrey, Institute for Obesity Research, Ave. Eugenio Garza Sada Sur 2501, C.P. 64849 Monterrey, N.L, Mexico; Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada Sur 2501, C.P. 64849 Monterrey, N.L, Mexico.
Tecnologico de Monterrey, Institute for Obesity Research, Ave. Eugenio Garza Sada Sur 2501, C.P. 64849 Monterrey, N.L, Mexico; Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada Sur 2501, C.P. 64849 Monterrey, N.L, Mexico; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, C.P. 64460 Monterrey, N.L, Mexico.
Comput Biol Med. 2024 Oct;181:109049. doi: 10.1016/j.compbiomed.2024.109049. Epub 2024 Aug 23.
Crotamine (Ctm) is a peptide isolated from Crotalus durissus terrificus venom. This molecule has been demonstrated to diminish body weight gain and enhance browning in adipose tissue, glucose tolerance, and insulin sensitivity; hence, it has been postulated as an anti-obesogenic peptide. However, the mechanism to elicit the anti-obesogenic effects has yet to be elucidated. Thus, we investigated the possible interaction of Ctm with receptors involved in obesity-related metabolic pathways through protein-protein docking and molecular dynamics refinement. To test the anti-obesogenic mechanism of Ctm, we selected and retrieved 18 targets involved in obesity-related drug discovery from Protein Data Bank. Then, we performed protein-protein dockings. The best three Ctm-target models were selected and refined by molecular dynamics simulations. Molecular docking demonstrated that Ctm was able to interact with 13 of the 18 targets tested. Having a better docking score with glucagon-like peptide-1 receptor (GLP-1R) (-1430.2 kcal/mol), DPP-IV (dipeptidyl peptidase-IV) (-1781.7 kcal/mol) and α-glucosidase (-1232.3 kcal/mol). These three models were refined by molecular dynamics. Ctm demonstrated a higher affinity for GLP-1R (ΔG: -41.886 ± 2.289 kcal/mol). However, Ctm interaction was more stable with DPP-IV (RMSD: 0.360 ± 0.015 nm, Radius of gyration: 2.781 ± 0.009 nm). Moreover, the number of interactions and the molecular mechanics energies of Ctm residues suggest that the interaction of Ctm with these receptors is mainly mediated by basic-hydrophobic dyads Y1-K2, W31-R32, and W33-R34. Together, all these results allow elucidating a possible molecular mechanism behind the previously described anti-obesogenic effects.
Crotamine (Ctm) 是从 Crotalus durissus terrificus 毒液中分离出来的一种肽。该分子已被证明可减少体重增加并增强脂肪组织的棕色化、葡萄糖耐量和胰岛素敏感性；因此，它被假定为一种抗肥胖肽。然而，诱发抗肥胖作用的机制尚未阐明。因此，我们通过蛋白质-蛋白质对接和分子动力学细化研究了 Ctm 与肥胖相关代谢途径中涉及的受体的可能相互作用。为了测试 Ctm 的抗肥胖机制，我们从蛋白质数据库中选择并检索了 18 个与肥胖相关药物发现相关的目标。然后，我们进行了蛋白质-蛋白质对接。选择并通过分子动力学模拟对最佳的三个 Ctm-靶标模型进行细化。分子对接表明，Ctm 能够与 18 个测试靶标中的 13 个相互作用。与胰高血糖素样肽-1 受体 (GLP-1R)（-1430.2 kcal/mol）、二肽基肽酶-4 (DPP-IV)（-1781.7 kcal/mol）和α-葡萄糖苷酶（-1232.3 kcal/mol）具有更好的对接评分。这三个模型通过分子动力学进行了细化。Ctm 对 GLP-1R 的亲和力更高（ΔG：-41.886±2.289 kcal/mol）。然而，Ctm 与 DPP-IV 的相互作用更稳定（RMSD：0.360±0.015 nm，回转半径：2.781±0.009 nm）。此外，Ctm 残基的相互作用数量和分子力学能量表明，Ctm 与这些受体的相互作用主要由碱性-疏水性偶极子 Y1-K2、W31-R32 和 W33-R34 介导。总之，所有这些结果都阐明了先前描述的抗肥胖作用背后的可能分子机制。
