Abstract:
Crotamine is a peptide isolated from the South American rattlesnake (Crotalus durissus terrificus) venom, it is proposed as anti-obesogenic bioactive due to its capability to diminish the body weight gain and modulate the carbohydrate and lipid metabolism in vivo. However, the mechanism to elicit the anti- obesogenic effects is not elucidated. Thus, to test the potential anti-obesogenic mechanism of Crotamine, we selected and retrieved from Protein Data Bank 18 targets involved in obesity-related drug discovery. Then, we performed Crotamine-target docking using ClusPro 2.0 web server. The best three Crotamine- target models were selected and refined by molecular dynamics simulations using GROMACS 19.6 software. The resulting dynamics were evaluated through binding energy, Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg). Molecular docking simulations demonstrated that Crotamine was able to interact with 13 of the 18 targets tested. Having the best docking scores when interacted with dipeptidyl peptidase- IV (DPP-IV) (-1,781.7 kcal/mol), glucagon-like peptide 1 receptor (GLP-1R) (-1,430.2 kcal/mol), and α- glucosidase (-1,232.3 kcal/mol). These three models were refined by molecular dynamics. Crotamine demonstrated to have a higher binding energy for GLP-1R (-41.88 ± 2.28 kcal/mol) than DPP-IV (-34.58 ± 4.05 kcal/mol) or α-glucosidase (-37.47 ± 6.65 kcal/mol). However, Crotamine interaction was more stablewithDPP-IV(RMSD:0.36±0.02nm,Rg:2.78±0.01nm)thanGLP 1R(RMSD:0.73±0.04nm,Rg:2.85±0.04 nm) or α-glucosidase (RMSD: 0.59 ± 0.06 nm, Rg: 3.04 ± 0.01 nm). Moreover, the number of interactions and the energetic contribution of Crotamine residues during dynamics demonstrated that the residues Y1, K2, K14, E15, K27, C30, R31, W32, R33, W34, K39, and G42 mediated the interaction with DPP-IV, GLP-1R, and α-glucosidase. From these residues, Y1-K2, R31-W32, and R33-W34 functioned as basic-hydrophobic dyads that lead the interaction. A mechanism of interaction described in scorpion and anemone toxins. Together, all these results demonstrated that Crotamine may elicit the anti-obesogenic effects through GLP- 1R or DPP-IV modulation.
Audience take away notes:
- The audience will be able to use this information to rationally design and develop new anti- obesity drugs, as our in silico results indicate that Crotamine has indeed specificity towards key molecular targets, eliciting potential anti-obesogenic effects.
- The results presented here will help to the audience to know about novel animal venom toxin- inspired drugs to treat obesity and other metabolic diseases such as insulin resistance. Which is its predicted metabolic target and how this peptide interacts.
- These findings provide a novel alternative for anti-obesity drug development, as several drugs that have been developed have limited efficacy, yet significant side effects such as cardiovascular and cerebrovascular problems, cancer, or psychological problems such as depression or suicidal ideation.
- Our results could help to the rational design of novel drug formulations to treat obesity.
