Discovery of novel small-molecule aldehyde dehydrogenase 2 activators based on drug repurposing

Abstract

Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the detoxification of reactive aldehydes under oxidative stress. Because an estimated 50% of East Asians carry a common ALDH2 deficient variant with decreased enzyme activity and are more susceptible to toxic aldehydes, more recent findings have highlighted the therapeutic potential of ALDH2 activators in aldehyde-related diseases such as cardiovascular injury. Drug repurposing has unique advantages in providing new lead compounds with good drug-like properties. Herein, we identified Tadalafil from DrugBank as a novel ALDH2 activator using a combination strategy of docking-based and pharmacophore-based virtual screening based on exploring the activation mechanism. Then a hit-based substructure search was completed and has led to the discovery of 5 hits, among which A1 showed better ALDH2 activation activity than Tadalafil. This study provides a good basis for the further research of ALDH2 activators.

Keywords

• Aldehyde dehydrogenase-2
• Activator
• Virtual screening
• Docking
• Pharmacophore
• Drug repurposing