Abstract
Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.
Highlights
Tuberous sclerosis, known as tuberous sclerosis complex (TSC) (OMIM 191100), is an autosomal dominant inherited disorder characterized by the presence of hamartomas in multiple organ systems, including the brain, kidney, heart, eyes, and skin [1]
Rheb, which is a major regulator of the mammalian target of rapamycin
Even everolimus has been used for years in treating there is cure still debate aboutthough the everolimus has been used for years in treating
Summary
Known as tuberous sclerosis complex (TSC) (OMIM 191100), is an autosomal dominant inherited disorder characterized by the presence of hamartomas (tumor-like lesions) in multiple organ systems, including the brain, kidney, heart, eyes, and skin [1]. TSC affects both sexes and multiple ethnic groups [1]. Its incidence and prevalence were estimated to be 1/10,000 live births and 1 in 6000 to 9000 individuals, respectively, and globally, at least two million people are affected [2]. TSC is due to the inactivating mutation in one of the TSC genes (TSC1 or TSC2). These TSC genes are tumor-suppressor genes [3] and play the role as a GTPase-activating protein (GAP) toward.
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