Polyoxygenated Cyclohexenes from Uvaria grandiflora with Multi-Enzyme Targeting Properties Relevant in Type 2 Diabetes and Obesity

Abstract

Shikimic acid-derived polyoxygenated cyclohexene natural products commonly occurring in several species of the Uvaria represent natural products with promising biological activities. While a number of derivatives have been reported from Uvaria grandiflora (U. grandiflora), further studies are needed to discover additional bioactive congeners, particularly derivatives with multi-protein target inhibitory properties implicated in diseases such as diabetes and obesity. In this paper, isolation and identification of a new highly oxygenated cyclohexene, uvagrandol (1), along with the known compound (-)-zeylenone (2) from the DCM sub-extract of U. grandiflora following in vitro and in silico assessment of their enzyme inhibitory properties against αglucosidase, dipeptidyl peptidase IV, porcine lipase, and human recombinant monoacylglycerol lipase are reported. The structure of 1 was elucidated using 1D and 2D NMR data analysis. The absolute configuration of 1 was established by quantum chemical calculations via the Gauge-Independent Atomic Orbital (GIAO) NMR method followed by TDDFT-Electronic Circular Dichroism (ECD) calculations. The structures of the eight possible stereoisomers were optimized by means of DFT calculations (B3LYP/6-31+G [d,p] in vacuum), and then their isotropic shielding tensors were obtained using the GIAO method at mPW1PW91/6-31G(d,p) in chloroform. Through DP4+, the isomer of configuration (1S,2S,3R,6R) for 1 was predicted with 96.3% probability. Compounds 1 and 2 significantly inhibited the four target enzymes in vitro. Binding studies through molecular docking simulations showed strong binding affinities for (-)-zeylenone (2), thus validating the in vitro results. Our findings suggest the potential of polyoxygenated cyclohexenes, in particular (-)-zeylenone (2), in anti-diabetic and anti-obesity drug discovery.

Cyclohexene oxide CA, a derivative of zeylenone, exhibits anti-cancer activity in glioblastoma by inducing G0/G1 phase arrest through interference with EZH2

“…Since its initial discovery in 1997, zeylenone has consistently demonstrated therapeutic potential against inflammation, diabetes, and various cancers, such as prostate, gastric, and cervical cancers ( Quimque et al, 2022 ). However, due to its multichiral centers and complex structure, zeylenone is somewhat difficult to synthetically obtain and to conformationally study ( Vinaykumar and Venkateswara Rao, 2021 ).…”

Antidiabetic potential of ethanolic crude extract of Garcinia atroviridis fruits: in vitro, in ovo, and in silico analysis

“…The X‐ray crystallographic structure of DPP‐4, α‐glucosidase, and α‐amylase were retrieved from Protein Data Bank (http://www.rcsb.org) with PDB IDs 2RIP, 2QMJ, and 3BAJ, respectively. These X‐ray crystallographic structures were extensively utilised in numerous earlier investigations (Chandrasekaran et al ., 2020; Gani et al ., 2021; Sharma et al ., 2021; Quimque et al ., 2022). Prior to generating PDBQT files for the targeted proteins, AutoDockTools 4.2 was employed to remove heteroatoms, optimise the structures, and add Kollman and polar hydrogen charges (Morris et al ., 2009).…”

Phytochemical Profiling and Assessment of Antidiabetic Activity of Curcuma Angustifolia Rhizome Methanolic Extract: An In Vitro and In Silico Analysis

“…Grid boxes were prepared and docking was conducted using autodock vina through the PyRx virtual screening tool [48] . The binding energy of each ligand was calculated and protein‐ligand interaction was visualized using PyMol and biovia discovery studio [49] …”

“…[48] The binding energy of each ligand was calculated and protein-ligand interaction was visualized using PyMol and biovia discovery studio. [49]…”