Structural optimization for pyrimidine analogues inhibitors against MAP kinase interacting serine/threonine kinase 1(MNK1) based on molecular simulation

Abstract MAP kinase interacting serine/threonine kinase 1 (MNK1) can promote the development of tumors through over-activation of MNK and phosphorylation of p-eIF4E, which is an important potential target for cancer therapy. A three-dimensional quantitative structure-activity relationship (3D-QSAR) is applied to investigate the relationship between activities and structures in this paper. Herein, a set of 73 4-aniline-thieno[2,3-d] pyrimidine derivatives were selected, and a 3D-QSAR study was performed by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) model in this paper. The experimental results shown that CoMFA (n = 10; q2 = 0.765; r2 = 0.979), CoMSIA (n = 10; q2 = 0.711; r2 = 0.967) had good stability and predictability. The relationship between the activity and structure of the compound was analyzed by counter maps of the steric, electrostatic and hydrophobic fields. Subsequently, molecular docking was applied to explore key amino acids and docking modes at the active site. Based on the results, 10 new 4-aniline-thieno[2,3-d] pyrimidine derivatives were designed and their activities were predicted. Afterwards, these molecules were submitted to further ADME studies, in which the ADME properties of the 10 designed molecules were found to be within a reasonable range. Molecular Dynamics (MD) simulation analysis confirmed that the residues Leu55, Val63, Lys126, Leu127, Gly130, Ser131, Leu177, Phe192 play a vital role in the active site. In addition, these compounds mainly to bind to MNK1 through lipophilic interactions and hydrogen bonding. These results provided important reference to the discovery and design of new MNK1 inhibitors.