Understanding the Structural Basis of ALDH-2 Inhibition by Molecular Docking

Background: The ALDH-2 enzyme has been identified as an important therapeutic target for the development of new drugs for the treatment of cocaine addiction. Several studies involving the synthesis, the design and pharmacological evaluation of daidzin (isoflavonoid inhibitor of ALDH-2) analogs were conducted. Methods: In this study, we used two in silico approaches effective to understand the mechanism of inhibition of ALDH-2 enzyme, the molecular docking and constructing a pharmacophore model, and we established a correlation between the inhibitory profiles of daidzin and its analog for ALDH-2 and their interaction profiles to understand the structural basis for their inhibitory activities. Results: Docking is efficient and opportune tool to guide the design of new inhibitors of ALDH-2. From the results of the molecular docking studies performed herein and their relationships with the inhibitory profiles of some daidzin analogs described previously in the literature, pharmacophore groups associated with ALDH-2 enzyme recognition were identified. Summarizing our findings, the presence of a linear alkyl chain with a terminal hydrogen bond acceptor group in position 7 is important for the interaction with the Gln-289 residue. Additionally, the presence of a group that is capable of performing hydrogen bonding interactions as either a donor or acceptor in the 4’ position is important for the interaction with the Glu-268 residue; this group is the primary pharmacophore that should be attached to the scaffold of the aromatic nucleus of an ideal inhibitor of ALDH-2. Conclusion: The structure inhibitory activity relationships among daidzin analogs were established using a molecular docking tool, thus identifying the structural reasons for the inhibition of the ALDH-2 enzyme. We defined the key pharmacophore groups required for enzyme inhibition and the maintenance of interactions with the amino acids Gln-289 and Glu-268, which are related to the potency of the ALDH-2 inhibitors. This study is highly relevant for the design of new ALDH-2 inhibitors using different medicinal chemistry tools to develop novel therapies for controlling cocaine addiction.