In silico design novel dihydropyrimio[4, 5-d]pyrimidine derivatives as inhibitors for colony-stimulating factor-1 receptor based on 3D-QSAR, molecular docking and molecular dynamics simulation

Abstract Colony-stimulating factor-1 receptor (CSF-1R) can affect the further development of tumors by regulating the generation and biological activity of mononuclear-phagocytic lineage cells, and is an important potential target for cancer treatment. In this study, we selected 48 dihydropyrimio [4, 5-d]pyrimidine derivatives and performed 3D-QSAR studies on them using CoMFA and CoMSIA model. The results showed that CoMFA (n = 10; q2 = 0.626; r2 = 0.998) and CoMSIA (n = 10; q2 = 0.684; r2 = 0.997) had good stability and predictability. The relationship between the activity and structure of the compounds was analyzed by counter maps of the steric, electrostatic and hydrophobic fields. Subsequently, molecular docking was used to explore key amino acids and docking modes at the active site. Based on these results, we designed 9 new dihydropyrimio [4, 5-d] pyrimidine derivatives and predicted their activities. The results indicated that these compounds had good predictive activities and ADME/T properties. MD simulation analysis confirmed that the residues Leu588 and Cys666 in the active site played a key role; at the same time, these compounds mainly bind to CSF-1R through hydrophobic interactions and hydrogen bonding. These results provided important reference for the discovery and design of new CSF-1R inhibitors.