Structure-Guide Design and Optimization of Potential Druglikeness Inhibitors for TGF beta RI with the Pyrrolopyrimidine Scaffold

Among all types of TGF beta 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 TGF beta RItypically 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 TGF beta RIinhibitors 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 TGF beta RIinhibitors. Finally, the highly druggable compound W8 was discovered and then synthesized, which inhibited TGF beta RIwith an IC50 value of about 10 mu M. In addition, the binding free energies (Delta G(bind)) of W8 (-42.330 +/- 3.341 kcal/mol) and BMS22 (-30.560 +/- 6.076 kcal/mol) indicate that the high binding affinity is not necessarily accompanied by high inhibitory activity. Last but not least, the per-residue interaction analysis revealed that the contribution energy of ASP351 to binding was the most significant difference between BMS22 and W8, -2.195 kcal/mol and 1.707 kcal/mol, respectively. As a result, increasing the affinity between SMKIs and ASP351 of TGF beta RImay effectively improve the inhibitory activity. The insights gained from this study could help with structure-guided optimization in searching for better SMKIs of TGF beta RI.