Discovery of a reversible ALDH1A3 inhibitor through a consensus docking-based virtual screening study

Aldehyde dehydrogenases (ALDHs) belong to a group of enzymes that play a vital role in various biological processes and cellular defence against aldehyde toxicity. The ALDH1A subfamily has largely been associated with elevated expression in cancer tissues, and in particular in cancer stem-like cells ALDH1A1 is a frequently expressed enzyme in stem cells and target for therapeutic intervention, however, other isoforms such as 1A2, 1A3, 2, 3A1 and 7A1 have drawn significant attention in the recent years due to their involvement in various pathophysiological conditions. The current study is aimed at therapeutic intervention of ALDH1A3 by developing new inhibitors with the aid of computer-assisted drug design approach. A mixed ligand- and structure-based virtual screening (VS) study employing 4 million compounds, was performed against the X-ray structure of ALDH1A3, supported by hierarchical and consensus docking employing 12 docking solutions, prediction of ADME properties, and binding free energy calculations, to identify new hit and selective compounds. One of the hit molecules (VS1) emerged as a new, and reversible inhibitor of ALDH1A3 from the biochemical screening and kinetic characterization. Molecular dynamics (MD) simulations further allowed us to distinguish between the protein-ligand dynamics of the VS hits and retinoic acid (RA) bound to ALDH1A3, establishing a correlation with the observed experimental results, further comparing with the reported ALDH1A3 inhibitors. VS1 can be used as a good starting point for structure-based hit optimization and hit-to-lead identification. The outcomes of this work are expected to benefit researchers working on computational and rational design of new ALDH inhibitors against cancer and other pathophysiological disorders.