Discovery of Novel Aldose Reductase Inhibitors Using a Protein Structure-Based Approach:  3D-Database Search Followed by Design and Synthesis

Abstract

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.

Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

“…Unfortunately, these were similar to known benzaldoximes with comparable inhibition constants [58]. Recently, Iwata et al published successful results of a 3D search followed by design and synthesis [59]. With the ADAM&EVE program [60], the 3D database of the Available Chemicals Directory was searched and 179 candidate compounds were obtained.…”

Computer‐Aided Drug Design

“…In general, scoring functions are divided into four categories: (1) force-fieldderived scoring functions considering nonbonded interactions (Jones et al, 1997;Weiner et al, 1984Weiner et al, , 1986 or solvations (Zhang et al, 1997;Shoichet et al, 1999); (2) regression-based scoring functions (Horton and Lewis, 1992;Böhm, 1998;Eldridge et al, 1997;Head et al, 1996); (3) knowledge-based scoring functions (Gohlke et al, 2000;Muegge and Martin, 1999;Verkhivker et al, 1995); and (4) other scoring functions including chemical scores, contact scores, or shape scores Nicklaus et al, 1995;Stouch and Jurs, 1986;Wang et al, 1998;Flower, 1998). FK506 binding protein (FKBP) ligand 14 (Burkhard et al, 1999), farnesyl transferase inhibitor 15 (Perola et al, 2000), HIV-1 RNA TAR inhibitor 16 (Filikov et al, 2000), and Aldose reductase inhibitors 17 (Iwata et al, 2001) are successful cases from docking ( Fig. 4.11).…”

Aldose Reductase Inhibitors

“…Computer modeling 76 -78 and three-dimensional database searches 79 have been performed based on X-ray structures. Thus novel inhibitors being structurally quite different from already-known inhibitors can be discovered by this means; furthermore, a drastic modification of a known inhibitor may also lead to more effective inhibitors.…”