Structure-Guide Design and Optimization of Potential Druglikeness Inhibitors for TGFβRI with the Pyrrolopyrimidine Scaffold.

ABSTRACT: Among all types of TGFβ signal blockers, small molecule kinase inhibitors (SMKIs) have attracted wide attention due to their economical production, obvious stability, and ease of oral administration. Nevertheless, SMKIs of TGFβRItypically have low druggability so there are none on the market. In this study, structure-based drug design (SBDD) was performed focusing on the pyrrolopyrimidin scaffold of BMS22 to find TGFβRIinhibitors with excellent medical potential. The binding mode, druggability, and target affinity were assessed by molecular docking, ADMET predictions, and molecular dynamics (MD) simulations for the designed TGFβRIinhibitors. Finally, the highly druggable compound W8 was discovered and then synthesized, which inhibited TGFβRIwith an IC₅₀ value of about 10 μM. In

SUBMITTER: Meng D 

PROVIDER: S-EPMC9653795 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature