Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

Abstract

Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening (VS) of potential IP–PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.

Computational identification of potential chemoprophylactic agents according to dynamic behavior of peroxisome proliferator-activated receptor gamma

“…38 All investigated systems are summarized in Table 1, and the details of simulation setup are in agreement with our previous work. 9,20,29 In brief, each system was solvated in a cubic box of SPC/E (simple-point-charge) water molecules extending at least 9.0 A from any solute atom. Na + counter-anions were placed to neutralize the system.…”

“…2 †), consistent with previous atomistic MD simulations of PPAR g -LBD with agonists. 9,29 As shown in Fig. 2, the representative conformations, extracted by RMSD clustering method, represent obvious structural differences.…”

“…[5][6][7] Existing evidence intensively indicates the latency of PPAR g agonists in lung cancer chemoprevention, and stimulates a viable pursuit in chemoprophylactic agents. 8,9 PPAR g ligand-binding domain (PPAR g -LBD), which is necessary and sufficient for the transcriptional activation, is composed of 13 a-helices (H1-H12 and H2 0 ), and includes a Yshaped internal ligand-binding pocket (LBP) and an activation function-2 surface (AF-2, formed by H3-5 and H12, see Fig. 1).…”

“…[23][24][25] To address this issue, a variety of algorithms and strategies have been developed for modeling receptor dynamics and minimizing disturbance of false positives, such as Markov state models (MSMs) and ensemble docking. [25][26][27][28] In our previous works, 9,29 we applied an ensemble-based docking method to determine the binding proles between ligands and PPAR g with the ideal computational costs. The outcomes aroused our interest to integrate and extend existing exible docking and conformational sampling methods to identify novel agents based on the dynamic behavior of PPAR g .…”

The Role and Regulation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

“…Based on the molecular pathways mentioned above, tyrosine kinase inhibitors (platelet-derived growth factor inhibitors) and serotonin antagonists are being explored, but present outcomes are not ideal. Moreover, ROCK inhibitors, VEGF receptor inhibitors, stem cell therapy, mTOR inhibitors, PPAR- γ agonist, and strategies aiming at Warburg effect are all in the early phase of research [ 15 , 142 – 144 , 151 , 152 ].…”