ArticleACS chemical biology2018
Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.
Article in ACS chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 91 citations in OpenAlex.
- Physiological basis of contraceptive function of a GSK3α-selective inhibitor, manifested during epididymal sperm maturation.Molecular human reproduction · 2026Article
- Identification and characterization of a novel aldehyde metabolite of WIN18,446 and associated WIN18,446-ALDH1A2 protein adducts using mass spectrometry.Drug metabolism reviews · 2026Article
- Reviewing the Implication of Aldehyde Dehydrogenases in Male Reproduction: Prospects for New Therapeutic Approaches.Pharmaceuticals (Basel, Switzerland) · 2026Review
- A scaffold repositioning approach: dihydroBenzoImidazoTriazineDione (BITD) derivatives as selective ALDH1A1 inhibitors.Molecular diversity · 2026Article
- From Discovery to Clinical Trial: YCT-529, an Oral NonHormonal Male Contraceptive Targeting the Retinoic Acid Receptor Alpha.Journal of medicinal chemistry · 2026Article
- Personalized polygenic profiling based on the genetic architecture of lipid metabolism in the Russian population.Frontiers in cardiovascular medicine · 2026Article
- Development of retinoid nuclear receptor pathway antagonists through targeting aldehyde dehydrogenase 1A3.iScience · 2025Article
- Integrated Approach of Machine Learning and High-Throughput Screening to Identify Chemical Probe Candidates Targeting Aldehyde Dehydrogenases.ACS pharmacology & translational science · 2025Article
- Discovery of a reversible ALDH1A3 inhibitor throwugh a consensus docking-based virtual screening study.Journal of computer-aided molecular design · 2025Article
- Analysis of individual patient pathway coordination in a cross-species single-cell kidney atlas.Nature genetics · 2025Article
- Non-hormonal Contraception: Current and Emerging Targets.Advances in experimental medicine and biology · 2025Review
- A genome-wide association study identifies new loci associated with response to SARS-CoV-2 mRNA-1273 vaccine in a cohort of healthy healthcare workers.Frontiers in immunology · 2025Article
- Emerging approaches to male contraception.Andrology · 2024Review
- The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes.The Journal of experimental medicine · 2024Review
- Molecular Bidents with Two Electrophilic Warheads as a New Pharmacological Modality.ACS central science · 2024Article
- Review
- Reversible Contraception in Males: An Obtainable Target?Biology · 2024Review
- Targeting nuclear receptor corepressors for reversible male contraception.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Determination of pharmacological inhibition of ALDH2 by ethanol clearance in mice.Toxicology and applied pharmacology · 2024Article
- Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits.Nature human behaviour · 2024Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in ( R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.