University of the Western Cape, School of Pharmacy, Bellville, South Africa.
South African Medical Research Council, Primate Unit and Delft Animal Centre (PUDAC), Cape town, South Africa.
BMC Pharmacol Toxicol. 2023 Nov 25;24(1):67. doi: 10.1186/s40360-023-00701-x.
Atherosclerosis is a form of cardiovascular disease that affects the endothelium of the blood vessel. Series of events are involved in the pathophysiology of this disease which includes the breaking down of the connective tissue elastin and collagen responsible for the tensile strength of the arterial wall by proteolytic enzyme. One of these enzymes called Cathepsin S (CatS) is upregulated in the progression of the disease and its inhibition has been proposed to be a promising pharmacological target to improve the prognosis of the disease condition. Asiatic acid and asiaticoside A are both pentacyclic triterpenoids isolated from Centella asiatica. Their use in treating various cardiovascular diseases has been reported.
In this study through in silico and in vitro methods, the pharmacokinetic properties, residue interaction, and inhibitory activities of these compounds were checked against the CatS enzyme. The SwissADME online package and the ToxTree 3.01 version of the offline software were used to determine the physicochemical properties of the compounds.
Asiatic acid reported no violation of the Lipinski rule while asiaticoside A violated the rule with regards to its molecular structure and size. The molecular docking was done using Molecular Operating Environment (MOE) and the S-score of - 7.25988, - 7.08466, and - 4.147913 Kcal/mol were recorded for LY300328, asiaticoside A, and asiatic acid respectively. Asiaticoside A has a docking score value (- 7.08466Kcal/mol) close to the co-crystallize compound. Apart from the close docking score, the amino acid residue glycine69 and asparagine163 both interact with the co-crystallized compound and asiaticoside A. The in vitro result clearly shows the inhibitory effect of asiaticoside and asiatic acid. Asiaticoside A has an inhibitory value of about 40% and asiatic acid has an inhibitory value of about 20%.
This clearly shows that asiaticoside will be a better drug candidate than asiatic acid in inhibiting the CatS enzyme for the purpose of improving the outcome of atherosclerosis. However, certain modifications need to be made to the structural make-up of asiaticoside A to improve its pharmacokinetics properties.
动脉粥样硬化是一种影响血管内皮的心血管疾病。该疾病的病理生理学涉及一系列事件，包括负责动脉壁拉伸强度的结缔组织弹性蛋白和胶原蛋白被蛋白水解酶分解。其中一种酶称为组织蛋白酶 S（CatS），在疾病进展中上调，其抑制作用被提议成为改善疾病预后的有前途的药物靶点。积雪草酸和积雪草苷 A 均为从积雪草中分离得到的五环三萜类化合物。它们在治疗各种心血管疾病中的应用已有报道。
在这项研究中，通过计算机模拟和体外方法，检查了这些化合物对 CatS 酶的药代动力学特性、残留相互作用和抑制活性。使用 SwissADME 在线包和 ToxTree 3.01 版本的离线软件来确定化合物的物理化学性质。
积雪草酸报告没有违反 Lipinski 规则，而积雪草苷 A 则违反了分子结构和大小的规则。分子对接使用分子操作环境（MOE）进行，记录的 S 评分分别为-7.25988、-7.08466 和-4.147913 Kcal/mol，用于 LY300328、积雪草苷 A 和积雪草酸。积雪草苷 A 的对接得分值（-7.08466 Kcal/mol）接近共晶化合物。除了接近的对接得分外，甘氨酸 69 和天冬酰胺 163 两个氨基酸残基都与共晶化合物和积雪草苷 A 相互作用。体外结果清楚地表明了积雪草苷和积雪草酸的抑制作用。积雪草苷 A 的抑制值约为 40%，积雪草酸的抑制值约为 20%。
这清楚地表明，积雪草苷将成为比积雪草酸更好的药物候选物，用于抑制 CatS 酶，以改善动脉粥样硬化的结果。然而，需要对积雪草苷 A 的结构进行某些修饰，以改善其药代动力学特性。
