Kimani Njogu M, Ochieng Charles O, Ogutu Mike Don, Yamo Kevin Otieno, Onyango Joab Otieno, Santos Cleydson B R
Department of Physical Sciences, University of Embu, Embu P.O. Box 6-60100, Kenya.
Department of Chemistry, Maseno University, Maseno P.O. Box 333-40105, Kenya.
J Xenobiot. 2023 Feb 21;13(1):102-120. doi: 10.3390/jox13010009.
Compounds from Engl. were previously reported for inhibitory activities of amylase and glucosidase enzymatic action on starch as a preliminary study toward the establishment of a management strategy against postprandial hyperglycemia, however, the inhibitory kinetics and molecular interaction of these compounds were never established. A study was thus designed to establish the inhibitory kinetics and in silico molecular interaction of α-glucosidase and α-amylase with metabolites based on Lineweaver-Burk/Dixon plot analyses and using Molecular Operating Environment (MOE) software, respectively. Skimmianine (), Norchelerythrine (), 6-Acetonyldihydrochelerythrine (), and 6-Hydroxy-N-methyldecarine () alkaloids showed mixed inhibition against both α-glucosidase and α-amylase with comparable to the reference acarbose ( > 0.05) on amylase but significantly higher activity than acarbose on α-glucosidase. One phenolic 2,3-Epoxy-6,7-methylenedioxyconiferol () showed a competitive mode of inhibition both on amylase and glucosidase which were comparable ( > 0.05) to the activity of acarbose. The other compounds analyzed and displayed varied modes of inhibition between noncompetitive and uncompetitive with moderate inhibition constants included chaylbemide A (), chalybeate B () and chalybemide C (), fagaramide (), ailanthoidol (), and sesame (). The important residues of the proteins α-glucosidase and α-amylase were found to have exceptional binding affinities and significant interactions through molecular docking studies. The binding affinities were observed in the range of -9.4 to -13.8 and -8.0 to -12.6 relative to the acarbose affinities at -17.6 and -20.5 kcal/mol on α-amylase and α-glucosidase residue, respectively. H-bonding, π-H, and ionic interactions were noted on variable amino acid residues on both enzymes. The study thus provides the basic information validating the application of extracts of in the management of postprandial hyperglycemia. Additionally, the molecular binding mechanism discovered in this study could be useful for optimizing and designing new molecular analogs as pharmacological agents against diabetes.
先前有报道称，来自Engl.的化合物对淀粉酶和葡萄糖苷酶作用于淀粉的活性具有抑制作用，这是建立餐后高血糖管理策略的初步研究，然而，这些化合物的抑制动力学和分子相互作用尚未确定。因此，设计了一项研究，分别基于Lineweaver-Burk/Dixon图分析并使用分子操作环境（MOE）软件，来确定α-葡萄糖苷酶和α-淀粉酶与代谢物的抑制动力学以及计算机模拟分子相互作用。Skimmianine（）、去甲白屈菜红碱（）、6-丙酮基二氢白屈菜红碱（）和6-羟基-N-甲基十氢萘酮（）生物碱对α-葡萄糖苷酶和α-淀粉酶均表现出混合抑制作用，对淀粉酶的抑制作用与参考药物阿卡波糖相当（P>0.05），但对α-葡萄糖苷酶的活性明显高于阿卡波糖。一种酚类化合物2,3-环氧-6,7-亚甲基二氧基松柏醇（）对淀粉酶和葡萄糖苷酶均表现出竞争性抑制模式，其活性与阿卡波糖相当（P>0.05）。分析的其他化合物表现出非竞争性和非竞争性之间的不同抑制模式，抑制常数适中，包括查莱贝米德A（）、查莱贝酸B（）和查莱贝米德C（）、法加酰胺（）、臭椿苦酮（）和芝麻素（）。通过分子对接研究发现，蛋白质α-葡萄糖苷酶和α-淀粉酶的重要残基具有特殊的结合亲和力和显著的相互作用。相对于阿卡波糖在α-淀粉酶和α-葡萄糖苷酶残基上的亲和力分别为-17.6和-20.5 kcal/mol，观察到的结合亲和力范围为-9.4至-13.8和-8.0至-12.6。在两种酶的可变氨基酸残基上均发现了氢键、π-氢键和离子相互作用。因此，该研究提供了基本信息，验证了Engl.提取物在餐后高血糖管理中的应用。此外，本研究中发现的分子结合机制可能有助于优化和设计新的分子类似物作为抗糖尿病药物。
