Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-12, Vol.27 (24), p.8773
• Main Authors: Zhou, Boqian, Zhang, Yongguang, Jiang, Wanyun, Zhang, Haiyang
• Format: Article
• Language: English
• Subjects: Addictions; alcohol addiction; Alcoholism; Aldehyde dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Butenafine; Computer applications; Crystal structure; Cytotoxicity; Dehydrogenase; Dehydrogenases; Dopamine; Drug addiction; Drug approval; drug repurposing; Drug screening; Drug use; Drugs; Electrostatic properties; Enzymes; FDA approval; Gene expression; Hydrophobicity; Indacaterol; Inhibitors; Kinases; Ligands; Metabolism; Mitochondria; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Polymorphism; Residues; Severe acute respiratory syndrome coronavirus 2; Simulation; Substance use; Substance use disorder; Toxicity; virtual screening
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27248773

Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge = +1 ) and olaparib ( = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor ( = -6 for ALDH2 plus the cofactor NAD ). This revealed a deficiency of the Vina scoring in dealing with strong charge-charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2.