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In-silico and in-vitro screening of Asiatic acid and Asiaticoside A against Cathepsin S enzyme
Temitope Akinwumi Ajani1, Kenechukwu Obikeze2, Zandisiwe E Magwebu3
1University of the Western Cape, School of Pharmacy, Bellville, South Africa. temitopeajani@gmail.com.
Insights
Asiaticoside A shows promise in inhibiting Cathepsin S (CatS) for atherosclerosis treatment, demonstrating a higher inhibitory effect than asiatic acid. Further structural modifications are suggested to optimize its pharmacokinetic properties for improved drug candidacy.
Area of Science:
- Biochemistry
- Pharmacology
- Medicinal Chemistry
Background:
- Atherosclerosis involves the breakdown of arterial wall components by enzymes like Cathepsin S (CatS).
- Cathepsin S (CatS) is upregulated in atherosclerosis, making its inhibition a potential therapeutic strategy.
- Asiatic acid and asiaticoside A from Centella asiatica are investigated for cardiovascular benefits.
Purpose of the Study:
- To evaluate the in silico and in vitro inhibitory potential of asiatic acid and asiaticoside A against Cathepsin S (CatS).
- To assess the pharmacokinetic properties and molecular interactions of these compounds with CatS.
- To determine the suitability of these compounds as drug candidates for atherosclerosis.
Main Methods:
- Physicochemical properties were determined using SwissADME and ToxTree software.
- Molecular docking studies were performed using Molecular Operating Environment (MOE).
- In vitro enzyme inhibition assays were conducted to measure the activity of asiatic acid and asiaticoside A against CatS.
Main Results:
- Asiaticoside A violated Lipinski's rule, while asiatic acid did not.
- Asiaticoside A exhibited a docking score of -7.08 kcal/mol, comparable to the co-crystallized ligand (-7.26 kcal/mol), and interacted with key residues.
- In vitro assays showed asiaticoside A inhibited CatS by ~40% and asiatic acid by ~20%.
Conclusions:
- Asiaticoside A demonstrates superior inhibitory activity against CatS compared to asiatic acid.
- Asiaticoside A is a more promising drug candidate for atherosclerosis treatment than asiatic acid.
- Structural modifications of asiaticoside A are recommended to enhance its pharmacokinetic profile.
Background:
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.
Methods:
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.
Result:
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%.
Conclusion:
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.
