5L2M

Structure of ALDH1A1 in complex with BUC11

Summary for 5L2M

• Entry DOI: 10.2210/pdb5l2m/pdb
• Related: 5L13 5L2N 5L2O
• Descriptor: Retinal dehydrogenase 1, YTTERBIUM (III) ION, 2,3,5-trimethyl-6-[3-oxo-3-(piperidin-1-yl)propyl]-7H-furo[3,2-g][1]benzopyran-7-one, ... (5 entities in total)
• Functional Keywords: aldh1a1 inhibitor, oxidoreductase-oxidoreductase inihbitor complex, oxidoreductase/oxidoreductase inihbitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 55516.55

Authors

Buchman, C.D.,Hurley, T.D. (deposition date: 2016-08-02, release date: 2017-03-08, Last modification date: 2024-11-06)

Primary citation

Buchman, C.D.,Hurley, T.D.
Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives.
J. Med. Chem., 60:2439-2455, 2017

PubMed Abstract: Aldehyde dehydrogenase 2 (ALDH2), one of 19 ALDH superfamily members, catalyzes the NAD-dependent oxidation of aldehydes to their respective carboxylic acids. In this study, we further characterized the inhibition of four psoralen and coumarin derivatives toward ALDH2 and compared them to the ALDH2 inhibitor daidzin for selectivity against five ALDH1/2 isoenzymes. Compound 2 (K = 19 nM) binds within the aldehyde-binding site of the free enzyme species of ALDH2. Thirty-three structural analogs were examined to develop a stronger SAR profile. Seven compounds maintained or improved upon the selectivity toward one of the five ALDH1/2 isoenzymes, including compound 36, a selective inhibitor for ALDH2 (K = 2.4 μM), and compound 32, which was 10-fold selective for ALDH1A1 (K = 1.2 μM) versus ALDH1A2. Further medicinal chemistry on the compounds' basic scaffold could enhance the potency and selectivity for ALDH1A1 or ALDH2 and generate chemical probes to examine the unique and overlapping functions of the ALDH1/2 isoenzymes.

PubMed: 28219011
DOI: 10.1021/acs.jmedchem.6b01825

Experimental method

X-RAY DIFFRACTION (1.7 Å)