Exploration of Resveratrol Derivatives as Novel Therapeutic Modulators of 11β-Hydroxysteroid Dehydrogenase 1 Activity in Metabolic Dysregulation.

Abstract

Background: Metabolic dysregulation, encompassing conditions such as type 2 diabetes mellitus, obesity, metabolic syndrome, and dyslipidemia, poses an increasing global health burden. The dysregulation of 11β-hydroxysteroid dehydrogenase 1 (11β- HSD1), a key enzyme in glucocorticoid metabolism, has been strongly implicated in the pathogenesis of these disorders by influencing glucose homeostasis, lipid metabolism, and insulin sensitivity. Consequently, targeting 11β-HSD1 offers a promising therapeutic strategy for mitigating metabolic dysregulation and its associated complications.

Aim: The study aimed to identify resveratrol derivatives with high binding affinity and inhibitory potential against 11β-HSD1, using computational approaches to evaluate their pharmacokinetic and toxicity profiles.

Methods: A library of resveratrol derivatives was screened using molecular docking to identify high-affinity compounds. The hit compounds were further evaluated for absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, followed by molecular dynamics simulations to assess their stability.

Results: The resveratrol cis-dehydrodimer emerged as the most promising candidate, demonstrating high binding affinity, favorable ADMET properties, and stability over a 200 ns simulation period. These findings suggest its potential as a small-molecule inhibitor of 11β-HSD1.

Conclusion: The resveratrol cis-dehydrodimer represents a viable candidate for further experimental validation as a therapeutic agent for metabolic disorders. Future studies should include synthetic validation and in vivo testing to confirm its efficacy.