Discovery of new oxadiazolo pyridine derivatives as potent ghrelin O-acyltransferase inhibitors using molecular modeling techniques

Diabesity is a major global health concern, and ghrelin O-acyltransferase (GOAT) acts as an important target for the development of new inhibitors of this disease. The present work highlights a detailed QSAR study using QSARINS software, which provides an excellent model equation using descriptors. Here, the best model equation developed has two variables, namely MLFER_E and XlogP, with statistical parameters R² = 0.8433, LOF = 0.0793, CCC_tr = 0.915, Q²_LOO = 0.8303, Q²_LMO = 0.8275, CCC_cv = 0.9081, R²_ext = 0.7712, and CCC_ext = 0.8668. A higher correlation of the key structural fragments with activity is validated by the developed QSAR model. Furthermore, molecular docking helped us identify the binding interactions. Thirty four new molecules with better predicted biological activity (pIC50) were designed. The binding energy of four compounds have shown higher binding activity into the membrane protein (PDB Id: 6BUG). Molecular dynamics simulation has established the stability of the protein-ligand complex over 100 ns. DFT and ADME-toxicity analyses also confirmed their drug-like properties. Based on our findings, we report that these new oxadiazolo pyridine derivatives lead to the development of potent candidates for further development.

Graphical abstract: METTL3-mediated HOTAIRM1 promotes vasculogenic mimicry in glioma via regulating IGFBP2 expression. METTL3 expression is high in glioma cells and tissues that stabilize and enhance HOTAIRM1 expression. This HOTAIRM1 then interacts with IGFBP2 which in turn promotes glioma cell malignancy and vasculogenic mimicry (VM) formation, thus providing a new direction for glioma therapy.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00167-z.