%0 Journal Article
%T Dissecting molecular mechanisms underlying the inhibition of β-glucuronidase by alkaloids from Hibiscus trionum: Integrating in vitro and in silico perspectives.
%A Kamel EM
%A Alkhayl FFA
%A Alqhtani HA
%A Bin-Jumah M
%A Rudayni HA
%A Lamsabhi AM
%J Comput Biol Med
%V 180
%N 0
%D 2024 Sep 31
%M 39089106
%F 6.698
%R 10.1016/j.compbiomed.2024.108969
%X β-Glucuronidase, a crucial enzyme in drug metabolism and detoxification, represents a promising target for therapeutic intervention due to its potential to modulate drug pharmacokinetics and enhance therapeutic efficacy. Herein, we assessed the inhibitory potential of phytochemicals from Hibiscus trionum against β-glucuronidase. Grossamide and grossamide K emerged as the most potent β-glucuronidase inhibitors with IC50 values of 0.73 ± 0.03 and 1.24 ± 0.03 μM, respectively. The investigated alkaloids effectively inhibited β-glucuronidase-catalyzed PNPG hydrolysis through a noncompetitive inhibition mode, whereas steppogenin displayed a mixed inhibition mechanism. Molecular docking analyses highlighted grossamide and grossamide K as inhibitors with the lowest binding free energy, all compounds successfully docked into the same main binding site occupied by the reference drug Epigallocatechin gallate (EGCG). We explored the interaction dynamics of isolated compounds with β-glucuronidase through a 200 ns molecular dynamics (MD) simulation. Analysis of various MD parameters revealed that grossamide and grossamide K maintained stable trajectories and demonstrated significant energy stabilization upon binding to β-glucuronidase. Additionally, these compounds exhibited the lowest average interaction energies with the target enzyme. The MM/PBSA calculations further supported these findings, showing the lowest binding free energies for grossamide and grossamide K. These computational results are consistent with experimental data, suggesting that grossamide and grossamide K could be potent inhibitors of β-glucuronidase.