Evaluation of the combination mode and features of p38 MAPK inhibitors: construction of different pharmacophore models and molecular docking

ABSTRACT

Abnormal expression of tumour necrosis factor-α (TNF-α) can lead to various pathological reactions, such as arthritis, psoriasis, krone disease, etc. p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transduction enzyme that plays important roles in influencing the release of intracellular TNF-α factor. It is very meaningful to study the targeting kinase with specific inhibitors in the treatment of related diseases. In order to achieve a deeper insight, it is necessary to analyse the structural characteristics and the action mode of the p38 MAPK inhibitors in the active site. In the study, a ligand-based common feature pharmacophore model and the receptor structure-based pharmacophore model were constructed, respectively. Their common chemical features consisted of the hydrophobic groups (H) and the hydrogen bond acceptors (A), and kept the consistency of spatial structure distribution. Then, the molecular docking and molecular dynamics simulation were performed with the eight training set compounds. The binding characteristics of molecules binding were described in the topological region of the active site. Finally, the structure–activity relationship (SAR) was obtained by analysing docking results with the different pharmacophore models. This research leads to the proposal of an interaction model in the p38 MAPK active site and provides guidance for the screening and design of more potent and selective p38 MAPK inhibitors.

KEYWORDS:

• p38 MAPK inhibitors
• targeting kinase
• pharmacophore model
• molecular docking

Acknowledgements

We also acknowledge the Shandong Collaborative Innovation Center for Antibody Drugs and Engineering Research Center for Nanomedicine and Drug Delivery systems for this support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81703357], [grant number 21473085]; the Shandong Provincial Natural Science Foundation [grant number ZR2017BH102]; Taishan Scholar Foundation of Shandong Province [grant number CIC-AD1837].