کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1394781 1501185 2010 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Aconitum and Delphinium alkaloids of curare-like activity. QSAR analysis and molecular docking of alkaloids into AChBP
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Aconitum and Delphinium alkaloids of curare-like activity. QSAR analysis and molecular docking of alkaloids into AChBP
چکیده انگلیسی

Early studies have shown that some of diterpenoid alkaloids, found in highly toxic plants of the genera Aconitum and Delphinium, act at neuronal nicotinic acetylcholine receptors (nAChRs) and exhibit potent N-cholinolytic activity. In the current study, GA-MLRA and GA-PLS approaches have been used to build QSAR models to predict N-cholinolytic activity measured in vivo (blockade of neuromuscular conductivity, BNMC and third eyelid relaxing activity, TYRA) and in vitro (suppression of frog’s abdominal straight muscles on acetylcholine, SAM) for a series of diterpenoid alkaloids. Random splitting of a data set (five trials in total) produced QSAR models of a good level of correlation between experimental in vitro/in vivo and calculated N-cholinolytic activity expressed as log(1/ED50) with following average statistical parameters: log BNMC (r2 = 0.87, s = 0.14, q2 = 0.82), log TYRA (r2 = 0.80, s = 0.29, q2 = 0.67), log SAM (r2 = 0.84, s = 29, q2 = 0.64). QSAR results suggest descriptors accounting for H-bond capability of molecules influence all three type of N-cholinolytic activity with additional contribution of steric and reactivity features as identified for TYRA and SAM data, respectively.The alkaloid-receptor complexes were further analyzed by means of AutoDock Vina docking program using the binding site of MLA complexed with AChBP (homolog of the ligand binding domain of nAChRs) as template. All compounds were shown to be well fitted in the binding pocket of native MLA with good correlation exhibited between their ED50 and AutoDock Vina binding free energy. An analysis of the possible factors significant for the ligand recognition has been enhanced by comparative docking studies performed for structurally related lycoctonine-type alkaloids (lappaconitine and aconitine) that are known to bind to voltage-gated Na+ channel, but not to nAChRs.

Classical QSAR and molecular docking approaches have been applied to reveal factors determining N-cholinolytic activity and AChBP-binding affinity of 19 curare-like Aconitum and Delphinium sp. alkaloids.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 45, Issue 9, September 2010, Pages 3885–3894
نویسندگان
, , , , ,