Discovery of Novel Glyoxalase-I Inhibitors Using Computational Fragment-Based Drug Design Approach

Nizar A. Al-Shar’i, Mohammad A. Hassan, Hadil M. Al-Barqi, Qosay A. Al-Balas, Tamam El-Elimat


In this study, a computational fragment-based drug design approach was employed to design potential glyoxalase-I (GLO-I) inhibitors. GLO-Iis overexpressed in various cancer types, which made it a viable target for cancer treatment. The current approach was based on screening the Maybridge Ro3 diversity fragment library using different computational techniques to select potential fragments that can be evoluted to putative drug-like active compounds. Six fragments were selected that are complementary to the main binding regions within the GLO-I active site. Fragments merging and linking had resulted in 21 potential GLO-I inhibitors. To assess the applicability of this approach, one pilot compound (12) was synthesized and biologically evaluated. The % of GLO-I inhibition by 12 at 50 µM was 44%,one fold lower than that of myricetin (86%) indicating that the utilized approach was successful. Despite the weak activity, the percent of inhibition of 12 can be extrapolated to get a rough estimate of the expected activities of other compounds within the evoluted set. Moreover, compound 12 could be considered as a new hit with a novel chemotype that can be further optimized towards designing more potent inhibitors.


Glyoxalase-I, Fragment-Based Drug Design, Zinc binding, Anticancer.

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