Homology modeling, molecular dynamics and virtual screening of endothelin-A receptor for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease of pulmonary arteries, causing serious shortness of breath and right ventricular failure with high mortality. Numerous studies have verified that the symptoms of PAH could be attenuated effectively with endothelin-A receptor (ETAR) antagonists. Unfortunately, the 3D structure of ETAR has not been released, making it difficult to understand the interactions between ETAR and its antagonists. In this study, computational methods including homology modeling, molecular docking and molecular dynamics simulations were performed to build the structure of ETAR and predict the binding patterns of ETAR with its two antagonists. Based on these results, virtual screening study was implemented against Traditional Chinese Medicine (TCM) database to identify novel natural ETAR antagonists. Six compounds with best binding energies were screened out and two of them were found to bind steadily with ETAR validated through molecular dynamics simulations and MM-GBSA calculation, indicating that they were potential antagonists of ETAR. In a word, our research provided a deep exploration into the interaction between ETAR and its antagonists, which could promote the development of novel therapy against PAH.[Formula: see text]Communicated by Ramaswamy H. Sarma.