Identification of Z/E Azobenzene Isomers with Putative Modulators of Cholesterol Biosynthesis Enzymes

Cardiovascular diseases (CVDs), responsible for over 18 million fatalities annually, remain a leading global cause of mortality. Atherosclerosis, driven by excess cholesterol accumulation and arterial plaque formation, underlies many of these conditions. The current treatment for these conditions (statins) targets inhibition at the early stages of cholesterol biosynthesis, depriving the body of other vital sterols from the pathway and causing several side effects in patients. In this study, we propose strategically targeting the terminal stages of cholesterol biosynthesis with the objective of identifying azobenzene derivatives with better binding score compared to native ligands of key enzymes: Squalene Monooxygenase (PDB ID: 6C6N), Lanosterol Synthase (1W6K and 1W6J), Sterol 14α-Demethylase (3K1O), and Cytochrome P450 51 (1H5Z). A structure-based computational approach was employed to explore E and Z azobenzene derivatives as putative modulators of these key enzymes involved in cholesterol biosynthesis. These enzymes represent essential checkpoints in sterol metabolism, making them attractive drug targets for cholesterol-lowering therapy. To explore novel scaffolds, we investigated E/Z azobenzene isomers, given their structural tunability and conformational flexibility, which can influence binding affinity and specificity. Through rigorous molecular docking analyses, several azobenzene-based compounds with enhanced binding profiles were identified and further examined using molecular dynamics (MD) simulations to qualitatively assess binding stability. The results indicate that azobenzene-based structures can be accommodated within predominantly hydrophobic sterol-processing enzyme pockets, forming stable noncovalent interactions under simulated conditions. Differences between E and Z isomers highlight conformational sensitivity in binding behaviour across enzyme targets. These findings collectively highlight the potential of E/Z azobenzene scaffolds as promising for further investigation as putative modulators of cholesterol biosynthesis pathways.