First report on chemometrics-driven multilayered lead prioritization in addressing oxysterol-mediated overexpression...

Contemporary research has convincingly demonstrated that upregulation of G protein-coupled receptor 183 (GPR183), orchestrated by its endogenous agonist, 7α,25-dihydroxyxcholesterol (7α,25-OHC), leads to the development of cancer, diabetes, multiple sclerosis, infectious, and inflammatory diseases. A recent study unveiled the cryo-EM structure of 7α,25-OHC bound GPR183 complex, presenting an untapped opportunity for computational exploration of potential GPR183 inhibitors, which served as our inspiration for the current work. A predictive and validated two-dimensional QSAR model using genetic algorithm (GA) and multiple linear regression (MLR) on experimental GPR183 inhibition data was developed. QSAR study highlighted that structural features like dissimilar electronegative atoms, quaternary carbon atoms, and CH₂RX fragment (X: heteroatoms) influence positively, while the existence of oxygen atoms with a topological separation of 3, negatively affects GPR183 inhibitory activity. Post assessment of true external set prediction capability, the MLR model was deployed to screen 12,449 DrugBank compounds, followed by a screening pipeline involving molecular docking, druglikeness, ADMET, protein-ligand stability assessment using deep learning algorithm, molecular dynamics, and molecular mechanics. The current findings strongly evidenced DB05790 as a potential lead for prospective interference of oxysterol-mediated GPR183 overexpression, warranting further in vitro and in vivo validation.