Resveratrol, a natural stilbene found in various plants, is mainly known for its strong antioxidant activities exhibiting a comprehensive range of treatments for some skin disorders such as skin cancer, photoaging, dermatitis, and melanogenesis. However, few studies have been conducted on the differences in biological activities between resveratrol and its derivatives. Therefore, we aimed to investigate the effects of resveratrol (Re) and its derivatives acetyl-resveratrol (Are), cis-trismethoxy resveratrol (Cre), dihydroresveratrol (Dre), and oxyresveratrol (Ore) on antioxidant and anti-tyrosinase effects using in vitro and in silico methods. In the in vitro results, Ore showed the highest antioxidant activity among the resveratrol derivatives and displayed stronger inhibitory activity against natural tyrosinase compared with that of kojic acid. Density functional theory (DFT) was used to calculate quantum chemical descriptors to understand the compounds’ electronic and physicochemical properties. Molecular docking and molecular dynamics simulations were also performed to explore the corresponding binding mode and structural behavior, revealing that Ore exhibited the strongest binding interactions among resveratrol derivatives, primarily through hydrogen bonds and hydrophobic interactions with key amino acid residues. Moreover, all the resveratrol compounds demonstrated drug-likeness properties with predicted safe skin toxicity profiles. In conclusion, Ore exhibited the strongest tyrosinase inhibition and antioxidant activity among resveratrol derivatives in both in vitro and in silico assessments. Further research on the development of medicines, cosmetics, and food supplements of such compounds should be conducted.

Hepatitis C virus (HCV) NS3/4A serine protease is a promising drug target for the discovery of anti-HCV drugs. However, its amino acid mutations, particularly A156T, commonly lead to rapid emergence of drug resistance. Paritaprevir and glecaprevir, the newly FDA-approved HCV drugs, exhibit distinct resistance profiles against the A156T mutation of HCV NS3/4A serine protease. To illustrate their different molecular resistance mechanisms, molecular dynamics simulations and binding free energy calculations were carried out on the two compounds complexed with both wild-type (WT) and A156T variants of HCV NS3/4A protease. QM/MM-GBSA-based binding free energy calculations revealed that the binding affinities of paritaprevir and glecaprevir towards A156T NS3/4A were significantly reduced by ∼4 kcal/mol with respect to their WT complexes, which were in line with the experimental resistance folds. Moreover, the relatively weak intermolecular interactions with amino acids such as H57, R155, and T156 of NS3 protein, the steric effect and the destabilized protein binding surface, which is caused by the loss of salt bridge between R123 and D168, are the main contributions for the higher fold-loss in potency of glecaprevir due to A156T mutation. An insight into the difference of molecular mechanism of drug resistance against the A156T substitution among the two classes of serine protease inhibitors could be useful for further optimization of new generation HCV NS3/4A inhibitors with enhanced inhibitory potency. Communicated by Ramaswamy H. Sarma