Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: In type 2 diabetes mellitus with obesity, both glycemic control and weight reduction are required; enhancing endogenous GLP-1 signaling has clinical value; TGR5 is an upstream target and the curcumin family has attracted attention but mechanistic evidence is scattered. Objectives: To evaluate, at structural and system levels, the mechanistic feasibility of the “curcumin–TGR5–GLP-1 axis” and to generate a prioritized ranking of candidates. Methods: Four human TGR5–Gs structures were used for redocking and Vina/GNINA consensus docking; based on the best poses, 200 ns×3 molecular dynamics (n=3) and MM-PBSA (100–200 ns) were performed; a GLP-1 module and a T2DM?obesity network were constructed to conduct enrichment, proximity and randomization tests; receptor reachability was assessed by integrating ADMET and R_direct evidence was integrated according to preregistered weights. Results: Redocking validated reliability (9GYO pass rate 85.00%, RMSD = 0.86 A; 7CFN 75.00%, 1.17 Å; 7XTQ 65.00%, 1.39 Å). The consensus ranking was INT-777 > tetrahydrocurcumin > curcumin; demethoxycurcumin and bisdemethoxycurcumin tied, followed by curcumin-glucuronide and curcumin-sulfate. Molecular dynamics showed Hyd-W237/Hyd-F96 occupancy about 55%–79%, late-phase (100–200 ns) Hyd-L71 about 70%–81%; Hbond-Y240 about 28%–36%, Hbond-N93 in the late phase (100–200 ns) about 30%–36%, with key interactions stabilizing at 70–100 ns. MM-PBSA indicated INT-777 ?28.94 kcal/mol, tetrahydrocurcumin ?24.63, curcumin ?18.72. Network statistics suggested closer inter-set adjacency: ?_obs = ?0.53 (Z = ?2.79, P_perm = 0.006), s_obs = ?0.58 (Z = ?2.76, P_perm = 0.008); enrichment was dominated by cAMP and G?s-related pathways (q < 0.05). R_direct classified INT-777 = 0.78 and tetrahydrocurcumin = 0.64 as favorable, with all others < 0.50. Conclusion: Curcumin modulating the GLP-1 pathway via TGR5 is mechanistically feasible; tetrahydrocurcumin ranks superior across structural, system and reachability dimensions and is a prioritized candidate for experimental validation; conclusions are limited to binding feasibility, mechanistic indications and prioritization.