Insights into the mechanism of crotamine and potential targets involved in obesity-related metabolic pathways

被引：0
作者：
Melendez-Martinez, David [1 ,2 ,4 ,4 ]
Morales-Martinez, Adriana [1 ,2 ,3 ,4 ,4 ,4 ]
Sierra-Valdez, Francisco [2 ]
Cossío-Ramírez, Raquel [2 ]
Lozano, Omar [1 ,3 ]
Mayolo-Deloisa, Karla [1 ,2 ]
Rito-Palomares, Marco [1 ,3 ]
Benavides, Jorge [1 ,2 ]
机构：
[1] Tecnologico de Monterrey, Institute for Obesity Research, Ave. Eugenio Garza Sada Sur 2501, N.L, Monterrey
[2] Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada Sur 2501, N.L, Monterrey
[3] Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, N.L, Monterrey
[4] Centro de investigación en Biotecnología, Universidad Autónoma del Estado de Morelos, Ave. Universidad 1001, Morelos, Cuernavaca
来源：
Computers in Biology and Medicine | 2024年 / 181卷
关键词：
Crotamine; Dipeptidyl peptidase-IV; Glucagon like peptide-1 receptor; Molecular dynamics; Obesity; α-glucosidase;
D O I：
10.1016/j.compbiomed.2024.109049
中图分类号：
学科分类号：
摘要：
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. © 2024 The Authors
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