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

Abstract

• A three-dimensional QSAR was insight into the structure-activity relationship of 4-aniline-thieno[2,3-d] pyrimidine derivatives (73compounds). • Steric, electrostatic, hydrophobic and hydrogen bond acceptor took into account simultaneously. • To understand the conformational stability and natural dynamics of the interaction in physiological environmental condition, compound 57/D1 and MNK1 were subjected to 100 ns MD simulation. • Theoretical calculations were carried out using density functional theory (DFT). • ADME property analysis also explored for in vivo applicability. 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; q 2 = 0.765; r 2 = 0.979), CoMSIA ( n = 10; q 2 = 0.711; r 2 = 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.