Ischak Netty Ino, Aman La Ode, Hasan Hamsidar, Kilo Akram La, Asnawi Aiyi
Chemistry Department, Universitas Negeri Gorontalo, Gorontalo, Indonesia.
Pharmacy Department, Universitas Negeri Gorontalo, Gorontalo, Indonesia.
Res Pharm Sci. 2022 Dec 24;18(1):100-111. doi: 10.4103/1735-5362.363616. eCollection 2023 Feb.
BACKGROUND AND PURPOSE: (AP) has long been used as an anti-diabetic agent, but the mechanism of action and active substance responsible for the anti-diabetic effect, particularly by inhibiting phosphodiesterase-9 (PDE9), which is one of the targets of anti-diabetic medications, have not been reported. The aim of the present study was to identify a new anti-diabetes candidate from secondary metabolite compounds of AP through PDE9 inhibition. EXPERIMENTAL APPROACH: In order to prepare the chemical structures of the secondary metabolites of AP and PDE9, docking and molecular dynamics simulations were run using Discovery Studio Visualizer, AutoDockTools, AutoDock, and Gromacs, along with a few other supporting software packages. FINDINGS/RESULTS: Molecular docking simulations showed that two of the 46 secondary metabolites of AP had higher free energies of binding, C00003672 (-11.35 kcal/mol) and C00041378 (-9.27 kcal/mol), than native ligand (-9.23 kcal/mol). The results of molecular dynamics showed that compound C00041378 interacted with TRY484 and PHE516, two active side residues of PDE9. ΔGMMGBSA interactions of PDE9 with C00003672, C00041378, and 49E compounds are 51.69, -56.43, and -48.13 kcal/mol, respectively, as well as ΔGMMPBSA interactions of PDE9 with C00003672, C00041378, and 49E compounds, were -12.26, -16.24, and -11.79 kcal/mol kcal/mol, respectively. CONCLUSIONS AND IMPLICATIONS: Based on the evaluations of AP secondary metabolites using docking and molecular dynamics simulation, it is suggested that the C00041378 compound has the potential to be an antidiabetic candidate by inhibiting PDE9.
背景与目的：穿心莲内酯（AP）长期以来一直被用作抗糖尿病药物，但其作用机制以及负责抗糖尿病作用的活性物质，特别是通过抑制磷酸二酯酶-9（PDE9），尚未见报道，而PDE9是抗糖尿病药物的靶点之一。本研究的目的是通过抑制PDE9，从穿心莲内酯的次生代谢产物化合物中鉴定一种新的抗糖尿病候选物。 实验方法：为了制备穿心莲内酯和PDE9的次生代谢产物的化学结构，使用Discovery Studio Visualizer、AutoDockTools、AutoDock和Gromacs以及其他一些支持软件包进行对接和分子动力学模拟。 研究结果：分子对接模拟显示，穿心莲内酯46种次生代谢产物中的两种具有比天然配体（-9.23 kcal/mol）更高的结合自由能，分别为C00003672（-11.35 kcal/mol）和C00041378（-9.27 kcal/mol）。分子动力学结果表明，化合物C00041378与PDE9的两个活性侧链残基TRY484和PHE516相互作用。PDE9与C00003672、C00041378和49E化合物的ΔGMMGBSA相互作用分别为51.69、-56.43和-48.13 kcal/mol，PDE9与C00003672、C00041378和49E化合物的ΔGMMPBSA相互作用分别为-12.26、-16.2
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