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.

Risk factors for portal vein stenosis in pediatric liver transplantation.

OBJECTIVE: To analyze the incidence and risk factors of portal vein stenosis (PVS) in pediatric liver transplantation (LT). METHODS: This retrospective analysis of 396 cases of pediatric LT (patients aged ≤ 14 years old) was conducted at the Liver Transplantation Center of Beijing Friendship Hospital (China) from June 2013 to December 2017. We collected relevant data and calculated the incidence. We analyzed a total of 23 risk factors for PVS children during the perioperative period. RESULTS: The incidence of PVS in pediatric LT was 6.6%. The following were identified as risk factors for PVS in pediatric LT: Preoperative portal hypertension was complicated, weight (≤7 kg), recipients of portal vein diameter ≤4 mm, GRWR (≥3.5%), the use of cold preservation vein grafts, anastomosis in the region of superior mesenteric vein and splenic vein and reverse blood flow in the portal vein shown in preoperative ultrasound examination. Recipients of portal vein diameter ≤4 mm and the use cold preservation grafts were independent risks factors for PVS in pediatric LT. CONCLUSION: For recipients with the risk factors identified in this study, we strongly recommend a strict follow-up and the provision of suitable interventions when indicated.

Identification of potential platelet-derived growth factor receptor α inhibitors by computational screening and binding simulations.

Platelet-derived growth factor receptor α (PDGFRα) is considered as a promising target for the treatment of fibrotic diseases. In this study, two types of pharmacophore model, which generated by ligand-based and receptor-based method, were put forward to identify novel chemical entities as PDGFRα inhibitors. It was found that some pharmacophore characteristics established by the two approaches overlap each other. In order to elucidate detailed interactions, representative molecules were selected to predict the conformations and binding modes of the molecules by molecular docking method. The calculation results of binding free energy illustrated that the van der Waals energy and nonpolar solvation were the most prominent contribution to the interactions between the inhibitors and PDGFRα. To further verify the accuracy of the docking results and the stability of the complexes system, the binding modes of two potent PDGFRα inhibitors were examined by 100 ns molecular dynamics simulations. Herein, we reported the basic structural requirements of PDGFRα inhibitors for the first time through molecular docking and molecular dynamics simulations. Subsequently, the two pharmacophore models were used for virtual screening to query potential active molecules from Food and Drug Administration approved database. The hit molecules here might provide additional scaffolds for further optimization of PDGFRα inhibitors.