The discovery of novel small molecule allosteric activators of aldehyde dehydrogenase 2.

Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35–45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N -benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo , which could reduce infarct size by ∼70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators. Image 1 • Novel allosteric activators of ALDH2 were found by computational virtual screening. • Ligand-based and structure-based parallel virtual screening strategy was used. • Compound C6 with good activity was discovered by further structural optimization. • Compound C6 could reduce infarct size by ∼70% in ischemic stroke rat models. [ABSTRACT FROM AUTHOR]