ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

6-amide-2-aryl benzoxazole/benzimidazole derivatives as VEFGR-2 inhibitors in two-and three-dimensional QSAR studies: topomer CoMFA and HQSAR

Jian-Bo Tong, Yi Feng, Ding Luo, and Tian-Hao Wang

College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi’an, People’s Republic of China

E-mail: 18590730858@163.com

Received: 13 November 2020  Accepted: 5 March 2021

Abstract:

The vascular endothelial growth factor (VEGF) is the main target of tumor treatment. VEGFR-2 is the main functional receptor of VEGF, which is involved in the regulation of angiogenesis. Based on hologram quantitative structure activity relationships (HQSAR) and topomer comparative molecular field analysis (topomer CoMFA), the contribution of 6-amide-2-aryl benzoxazole/benzimidazole derivatives (VEGFR-2 kinase inhibitors) to these structures was discussed and the corresponding modification strategies were proposed. The most effective HQSAR and topomer CoMFA models are generated by using a training set of 33 compounds. In order to ensure the robustness of the model, the randomization test was used, and 11 compounds were selected as the test set. The results show that the q² of cross-validation is 0.646/0.659, and the r² of non-cross-validation is 0.871/0.867, respectively. The data show that both models are reliable. Topomer CoMFA’s steric/electrostatic contour and HQSAR’s atomic contribution map show the structural characteristics controlling its inhibition ability. In addition, molecular docking is also used to study the interaction between these drugs and large proteins, and the ligand pair is connected to the active site of VEGFR-2 kinase, revealing the possible biological active conformation. This study showed that there was a wide interaction between 6-amide-2-aryl benzoxazole/benzimidazole derivatives and Hrg136 and Tyr356 residues of VEGFR-2 kinase active site. Finally, we used ADMET properties and drug-like properties to predict the newly designed molecules, and the results showed that they meet the conditions for becoming drugs and are expected to become potential anti-VEGFR-2 inhibitors. This study can provide a theoretical reference for the synthesis of target products of VEGFR-2 inhibitors.

Keywords: VEGFR-2; 6-Amide-2-aryl benzoxazole/benzimidazole derivatives; HQSAR; Topomer CoMFA; Molecular dock; ADMET

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-021-01588-w

Chemical Papers 75 (7) 3551–3562 (2021)