Structural alterations in the catalytic core of hSIRT2 enzyme predict therapeutic benefits of Garcinia mangostana derivatives in Alzheimer's disease: molecular dynamics simulation study

Recent studies have shown that inhibition of the hSIRT2 enzyme provides favorable effects in neurodegenerative diseases such as Alzheimer's disease. Prenylated xanthone phytochemicals including α-mangostin, β-mangostin and γ-mangostin obtained from Garcinia mangostana, a well-established tropical plant, have been shown experimentally to inhibit sirtuin enzymatic activity. However, the molecular mechanism of this sirtuin inhibition has not been reported. Using comprehensive integrated computational techniques, we provide molecular and timewise dynamical insights into the structural alterations capable of facilitating therapeutically beneficial effects of these phytochemicals at the catalytic core of the hSIRT2 enzyme. Findings revealed the enhanced conformational stability and compactness of the hSIRT2 catalytic core upon binding of γ-mangostin relative to the apoenzyme and better than α-mangostin and β-mangostin. Although thermodynamic calculations revealed favorable binding of all the phytochemicals to the hSIRT2 enzyme, the presence of only hydroxy functional groups on γ-mangostin facilitated the occurrence of additional hydrogen bonds involving Pro115, Phe119, Asn168 and His187 which are absent in α-mangostin- and β-mangostin-bound systems. Per-residue energy contributions showed that van der Waals and more importantly electrostatic interactions are involved in catalytic core stability with Phe96, Tyr104 and Phe235 notably contributing π–π stacking, π–π T shaped and π–sigma interactions. Cumulatively, our study revealed the structural alterations leading to inhibition of hSIRT2 catalysis and findings from this study could be significantly important for the future design and development of sirtuin inhibitors in the management of Alzheimer's disease.