ABSTRACT
In this research, a combined method of ligand-based pharmacophore (LBP), structure-based pharmacophore (SBP), and molecular docking was applied for virtual screening potential ATP-sensitive potassium channel (KATP) openers from Chinese herbs. LBP models were generated by 3D-QSAR pharmacophore(hypogen) program, based on the training set composed of 48 KATP agonists. The best LBP model consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic feature, one aromatic ring and five excluded volumes. Besides, the correlation coefficient of training set and test set, N, and CAI value of the model were 0.876 4, 0.705 8, 3.304, and 2.616 respectively. Meanwhile, SBP models were also generated based on a 3D structure of KATP (PMID: PM0079770). The best SBP model consisted of six hydrogen-bond acceptors, eight hydrogen-bond donors, seven hydrophobic features and eighteen excluded volumes. The corresponding N and CAI value were 2.200 and 2.017. Then, the best LBP model and SBP model were applied to identify potential KATP openers from Traditional Chinese Medicine Database(TCMD), respectively. 349 hits were obtained after analyzed by drug-likeness rules. Moreover, 12 compounds with high docking scores were reserved after molecular docking evaluation. Interestingly, part of the results had been verified as hypotensive active ingredients by literatures. Therefore, this study uncovers a specific target effect contained in TCMD, and provides candidates for new KATP openers' research.
ABSTRACT
Background: Diabetes mellitus is associated with many cardiovascular dysfunction and impairment of potassium channel function. Aim: We compared the vascular reactivity in aorta from streptozotocin-induced and Goto-Kakizaki (GK) diabetic rats to potassium channel openers. Methodology: Diabetes mellitus (DM) was induced in Sprague Dawley rats by intraperitoneal injection of streptozotocin (STZ) at 65 mg/kg body weight. After four weeks of DM, vascular reactivity of the aortic rings from STZ-induced Sprague Dawley and age-matched GK and control rats to phenylephrine, acetylcholine, levcromakalim and naringenin was studied using standard organ bath procedure. Results: The phenylephrine-induced contraction was significantly (P<0.05) increased in STZ-diabetic aortic rings [2.03 ±0.07 g] when compared with GK rats [1.47±0.14 g] and STZ-control [1.42±0.21 g]. Maximal relaxation and potency to acetylcholine, levcromakalim and (+/-)-naringenin were significantly (P<0.05) decreased in STZdiabetic aorta when compared with GK-diabetic and control groups. Conclusion: The phenylephrine-induced contraction, endothelium-dependent relaxation, KATP - and (+/-)-naringenin-induced vasorelaxation are not altered in the early stages of Type 2 diabetes whereas there is exaggerated contractile response and a relaxant dysfunction involving the endothelium, KATP in Type 1 diabetes mellitus.
ABSTRACT
ATP sensitive potassium channel(K ATP has been indentified in a variety of tissues and recognized as an important drug target.K ATP channels is composed with a 4∶4 stoichiometry of an inwardly rectifying K + channel(Kir) subunit plus a sulfonylurea receptor(SUR).The characteristics for the SUB2B/Kir 6 1 in vascular are small condutance,ATP insensitivity and activation by added NDP.Therefore,it is refered as NDP dependent K + channel(K NDP ).A lot of endogenous and exogenous vasodilators seem to act through a common pathway by opening K ATP in vascular,which is involved in protein kinase A and C signal transduction pathway.Vascular shows different sensitivity to potassium channel openers(KCO),and the mechanism remains to be determined.In this review,a summary of K ATP in vascular is presented with molecular structure,KCO selectivity to tissue,signal pathway,electrophysiological and pharmacological properties.