Pakistan journal of pharmaceutical sciences · 2026
Network pharmacology combined with molecular docking to investigate the potential role of curcumin targeting TGR5 to modulate the GLP-1 pathway in T2DM with obesity.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhao Chengyi, Shang Juju
Аннотация
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<sub>direct<|sub> 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: δ_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 Gαs-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.
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<sub>direct<|sub> 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: δ_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 Gαs-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.