ABSTRACT
Two new benzophenones: garcimangophenones A (6) and B (7) and five formerly reported metabolites were purified from the pericarps EtOAc fraction of Garcinia mangostana ((GM) Clusiaceae). Their structures were characterized by various spectral techniques and by comparing with the literature. The α-amylase inhibitory (AAI) potential of the isolated metabolites was assessed. Compounds 7 and 6 had significant AAI activity (IC50 9.3 and 12.2 µM, respectively) compared with acarbose (IC50 6.4 µM, reference α-amylase inhibitor). On the other hand, 5 had a moderate activity. Additionally, their activity towards the α-amylase was assessed utilizing docking studies and molecular dynamics (MD) simulations. The docking and predictive binding energy estimations were accomplished using reported crystal structure of the α-amylase (PDB ID: 5TD4). Compounds 7 and 6 possessed highly negative docking scores of -11.3 and -8.2 kcal/mol, when complexed with 5TD4, respectively while acarbose had a docking score of -16.1 kcal/mol, when complexed with 5TD4. By using molecular dynamics simulations, the compounds stability in the complexes with the α-amylase was analyzed, and it was found to be stable over the course of 50 ns. The results suggested that the benzophenone derivative 7 may be potential α-amylase inhibitors. However, further investigations to support these findings are required.
ABSTRACT
Small molecular chemicals targeting individual subtype of G proteins including Gs, Gi/o and Gq has been lacking, except for pertussis toxin being an established selective peptide inhibitor of the Gi/o protein. Recently, a cyclic depsipeptide compound YM-254890 isolated from culture broth of Chromobacterium sp. was reported as a selective inhibitor for the Gq protein by blocking GDP exchange of GTP on the α subunit of Gq complex. However, functional selectivity of YM-254890 towards various G proteins was not fully characterized, primarily due to its restricted availability before 2017. Here, using human coronary artery endothelial cells as a model, we performed a systemic pharmacological evaluation on the functional selectivity of YM-254890 on multiple G protein-mediated receptor signaling. First, we confirmed that YM-254890, at 30 nM, abolished UTP-activated P2Y2 receptor-mediated Ca2+ signaling and ERK1/2 phosphorylation, indicating its potent inhibition on the Gq protein. However, we unexpectedly found that YM-254890 also significantly suppressed cAMP elevation and ERK1/2 phosphorylation induced by multiple Gs-coupled receptors including ß2-adrenegic, adenosine A2 and PGI2 receptors. Surprisingly, although YM-254890 had no impact on CXCR4/Gi/o protein-mediated suppression of cAMP production, it abolished ERK1/2 activation. Further, no cellular toxicity was observed for YM-254890, and it neither affected A23187- or thapsigargin-induced Ca2+ signaling, nor forskolin-induced cAMP elevation and growth factor-induced MAPK signaling. We conclude that YM-254890 is not a selective inhibitor for Gq protein; instead, it acts as a broad-spectrum inhibitor for Gq and Gs proteins and exhibits a biased inhibition on Gi/o signaling, without affecting non-GPCR-mediated cellular signaling.
