Fragment-Based Design of the Potential AlkBH5 Inhibitors

Abstract

Background. AlkBH5 is a mammalian demethylase responsible for removal of m6A (N6-methyladenosine) modification in RNA. Multiple studies have proven the role of AlkBH5 in several malignancies. Downregulation of demethylase activity using small-molecule ligands has therapeutic potential. Aim. Fragment-based drug design of AlkBH5 inhibitors using different computer-aided drug design techniques. Methods. The library of new potential active compounds was designed using the Core Hopping procedure on the basis of structure analysis of the previously reported active compounds. The interaction between target and designed ligands was evaluated using molecular docking, molecular dynamics simulation, and MM-GBSA calculations. Results. Eight potentially active compounds were identified and selected for the further biological evaluation. Three of them were predicted as the most promising candidates. Conclusion. The study successfully implemented fragment-based methods of computer-aided drug design to identify potential compounds that can be active against AlkBH5.