Analysis of Compounds Isolated from Gnetum gnemon L. Seeds as Potential ACE Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Abstract

2Hypertension is a condition in which arterial blood pressure is continuously elevated. To be diagnosed with hypertension when one's systolic pressure is higher than 140 mm Hg, and the diastolic pressure reaches greater than or equal to 90 mm Hg.3 Hypertension affects about 40% of people aged 25 years or older, both in developing countries, and developed countries. 4 Hypertension is a leading problem in Indonesia, because of the high prevalence and the long term effect. 5 In 2013, Indonesia has 25.8% prevalence of adult over 18 years with hypertension based on blood pressure measurements using the sphygmomanometer. 6 The majority of hypertensive patients rely on ACE (angiotensin-converting enzyme) inhibitors in managing their conditions. 7 Angiotensin-converting enzyme (ACE) plays an inportant role in the conversion of angiotensin I to angiotensin II, a known potent vasoconstrictor.8 Furthermore, angiotensin II increases blood pressure which is the significant risk factor for hypertension. 3Gnetum gnemon L. (melinjo) is a plant that spreads in Southeast Asia, Melanesia, and the Pacific Islands. This tree has a height of 10-15 meters, with a slender-shaped trunk with a diameter of approximately 40 cm. This plant has one oval-shaped seed on each fruit.9 Melinjo belongs to Gnetum (Gnetaceae) genus plant, which is known containing many stilbene derivatives. 10-12Gnetum gnemon L. seed extracts have been known to have some biological activities. 13 The previous research showed that the ethyl acetate extract of melinjo seed had the highest inhibitory activity towards ACE compared to other extraction solvents in vivo.14 Furthermore, there are compounds found in the ethyl acetate extract of melinjo seed such as resveratrol, gnetol, isorhapontigenin, trans-piceid, gnetin C, trans-ε-viniferin, gnemonol M, gnemonol K, gnemonoside A, gnemonoside B, gnemonoside C, gnemonoside D, and latifolol. A recent research demonstrated that several compounds of melinjo seed extracts have a better affinity than lisinopril to ACE based on molecular docking results using AutoDock Vina.15 Therefore, this study conducted a further analysis of the ligand binding to amino acid residues at ACE active sites and the ligand binding to Zn 2+ ions, which both of these mechanisms are important in ACE inhibition. 16 These two essential interactions were analyzed through molecular docking using AutoDock4Zn, which generates more accurate free energy binding calculations than AutoDock Vina on ligand-Zn interactions.17 Molecular dynamics simulations were also conducted, involving several compounds in melinjo seed within 20 ns to check the stability of the ligand-enzyme complexes. ABSTRACTObjective: Gnetum gnemon L. (melinjo) seed extracts have been known to have some biological activities. One of them is ACE (angiotensinconverting enzyme) inhibitor. The present study was conducted to predict potential ACE inhibitory activity of several compounds isolated from Gnetum gnemon L. seeds by using in silico method. Methods: In this study, several compounds isola...

Screening and molecular dynamics simulation of ACE inhibitory tripeptides derived from milk fermented with Lactobacillus delbrueckii QS306

“…The free energy binding (ΔG) value of Captopril to ACE at 310 K calculated based on MM-PBSA was −14.89 kcal mol −1 . 38 Captopril was a small compound containing sulfhydryl group, and it was found that captopril forms hydrogen bond with amino acid Gln 281 His 353 Glu 384 His 513 Tyr 520 Lys 511, the active site of ACE. 39,40 The comparison shows that the results of molecular docking and molecular dynamics simulations of WRP, WSR and YRP were good, which can be further verified.…”