Sàng lọc ảo các chất có khả năng ức chế phosphodiesterase 9 ứng dụng trong điều trị Alzheimer

Abstract

In view that phosphodiesterase 9 (PDE9) inhibitors are potentially applied in the treatment of Alzheimer's disease, 2D-QSAR, 3D-pharmacophore and molecular docking models were developed for virtual screening of new PDE9 inhibitors. The 2D-QSAR model was built on a database collection of 477 PDE9 inhibitors from 8 scientific papers and individual 15 patents. The HipHop algorithm was used to create the 3D-pharmacophore models based on a database of six strong Inhibitors. The molecular docking studies were performed on PDE9 structures (pdb 4Y86). These 3 models were applied to virtual screening for new PDE9 inhibitors on 6 databases inclusive of 380,330 compounds. By the virtual screening, three compounds of various structural frames were found having highly predicted PDE9 inhibitory activity (predicted IC₅₀ ≤ 50 nM). This may provide the basis for designing novel PDE9 inhibitors able of crossing the blood-brain barrier and granting high safety.