Discovery of novel aldose reductase inhibitors using a protein structure-based approach: 3D-database search followed by design and synthesis.
Aldose reductase (AR) has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out structure-based drug design and synthesis in an attempt to find new types of AR inhibitors. With the ADAM&EVE program, a three-dimensional database (ACD3D) was searched using the ligand binding site of the AR crystal structure. Out of 179 compounds selected through this search followed by visual inspection, 36 compounds were purchased and subjected to a biological assay. Ten compounds showed more than 40% inhibition of AR at a 15 microg/mL concentration. In a subsequent lead optimization, a series of analogues of the most active compound were synthesized based on the docking mode derived by ADAM&EVE. Many of these congeners exhibited higher activities compared to the mother compound. Indeed, the most potent, synthesized compound showed an approximately 20-fold increase in inhibitory activity (IC(50) = 0.21 vs 4.3 microM). Furthermore, a hydrophobic subsite was newly inferred, which would be useful for the design of inhibitors with improved affinity for AR.
Iwata
Y
Y
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Arisawa
M
M
Hamada
R
R
Kita
Y
Y
Mizutani
M Y
MY
Tomioka
N
N
Itai
A
A
Miyamoto
S
S
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; C427734:succinic acid benzyl ester 3-carboxymethyl-1-(4-chlorobenzoyl)-2-methylindol-5-yl ester; D000449:Aldehyde Reductase