Computational Analysis of ELOVL6 Structure and Inhibition for Rational Drug Design.

ELOVL6 is a key enzyme in long-chain fatty acid elongation, catalyzing the conversion of C16 fatty acids into C18 fatty acids. While its role in lipid metabolism is well established, recent studies have linked ELOVL6 to metabolic and neurodegenerative diseases, making it an attractive therapeutic target. However, the absence of a resolved crystal structure and limited mechanistic understanding of its inhibition pose significant challenges for drug discovery. In this study, we employ a multitiered computational approach, including structure prediction, molecular dynamics (MD) simulations, and free energy calculations, to investigate the structural basis of ELOVL6 function and inhibition. We identify the most thermodynamically favorable substrate binding pathway and characterize key conformational changes associated with ligand binding. By analyzing potential inhibitor binding pockets, we determine that known inhibitors preferentially target the active site, and we validate their binding affinities against experimental data. Additionally, by comparing ELOVL6 with homologous elongases, we pinpoint potentially key amino acid residues responsible for selectivity, providing insights that could guide structure-based drug design. Our findings establish a mechanistic framework for rational inhibitor development, offering a foundation for future efforts in optimizing ELOVL6-targeting therapeutics.