PDF(Pubmed)
Abstract：
Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba\'s compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = -8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = -7.84 kcal/mol; Ki = 7.96µM). From ashitaba\'s compounds, it was found that 4\'-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3\'-carboxymethyl-4,2\'-dihydroxy-4\'-methoxychalcone have low ΔG of below -6 kcal/mol. The lowest ΔG value was found in 3\'-carboxymethyl-4,2\'-dihydroxy-4\'-methoxy chalcone with a ΔG of -6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = -5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = -6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity.
摘要：
他汀类药物是降胆固醇药物，具有抑制3-羟基-3-甲基戊二酰辅酶A还原酶的机制，但是长期使用会引起副作用。能够降低胆固醇水平的植物的实例是Angelicakeiskei(ashitaba)。因此,本研究旨在通过计算机模拟试验，从ashitaba中获得对HMG-CoA还原酶具有抑制活性的合适化合物。实验从筛选和药效团建模开始，然后在ashitaba的化合物上进行分子对接，他汀类药物组，天然配体是(3R，5R)-7-[4-(苄基氨基甲酰基)-2-(4-氟苯基)-5-(1-甲基乙基)-1H-咪唑-1-基]-3,5-二羟基庚酸(4HI)。根据分子对接模拟的结果，15个命中化合物具有小的结合能(ΔG)。匹伐他汀,作为比较药物（ΔG=-8.24kcal/mol；Ki=2.11µM），具有比天然配体4HI更低的ΔG和抑制常数（Ki）（ΔG=-7.84kcal/mol；Ki=7.96µM）。从阿希塔巴的化合物中，发现了4'-O-香叶柚皮素,木犀草素,异叶瓦查酮,多斯曼宁A,和3'-羧甲基-4,2'-二羟基-4'-甲氧基查耳酮具有低于-6千卡/摩尔的低ΔG。在3'-羧甲基-4,2'-二羟基-4'-甲氧基查耳酮中发现了最低的ΔG值，ΔG为-6.67kcal/mol，Ki值为16.66µM，低于其他比较药物的ΔG值，阿托伐他汀(ΔG=-5.49kcal/mol;Ki=1148.17µM)和辛伐他汀(ΔG=-6.50kcal/mol;Ki=22.34µM)。该化合物还与重要的氨基酸残基结合，包括ASN755D,ASP690C,GLU559D,LYS735D,LYS691C,SER684C,通过氢键根据结果,该化合物以良好的结合亲和力有效地结合六个重要的氨基酸，并且只需要很小的浓度就可以降低一半的酶活性。
