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

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• Aldehyde dehydrogenases (ALDHs) are crucial enzymes involved in cellular defense and biological processes.
• The ALDH1A subfamily, particularly ALDH1A1 and ALDH1A3, is implicated in cancer and other pathophysiological conditions.
• Targeting ALDH1A3 represents a potential therapeutic strategy for various diseases.

Purpose of the Study:

• To design and identify novel inhibitors of aldehyde dehydrogenase 1A3 (ALDH1A3) using a computer-assisted drug design approach.
• To discover selective and potent ALDH1A3 inhibitors for potential therapeutic applications.
• To provide a starting point for hit optimization and hit-to-lead development for ALDH1A3 inhibitors.

Main Methods:

• A mixed ligand- and structure-based virtual screening (VS) of 4 million compounds against the ALDH1A3 X-ray structure.
• Hierarchical and consensus docking employing 12 docking solutions.
• Prediction of ADME properties, binding free energy calculations, biochemical screening, kinetic characterization, and molecular dynamics (MD) simulations.

Main Results:

• Identification of a novel, reversible ALDH1A3 inhibitor, designated VS1, through virtual screening and biochemical assays.
• Molecular dynamics simulations provided insights into protein-ligand dynamics, correlating with experimental findings.
• VS1 serves as a promising starting point for further structure-based optimization and development of ALDH1A3 inhibitors.

Conclusions:

• The study successfully identified a novel ALDH1A3 inhibitor (VS1) using a comprehensive computational and experimental approach.
• The findings support the potential of VS1 as a scaffold for developing new therapeutic agents targeting ALDH1A3.
• This work is expected to advance the rational design of ALDH inhibitors for cancer and other disorders.