کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1361402 981462 2007 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Estimation of hERG inhibition of drug candidates using multivariate property and pharmacophore SAR
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Estimation of hERG inhibition of drug candidates using multivariate property and pharmacophore SAR
چکیده انگلیسی

We describe the development of a computational model for the prediction of the inhibition of K+ flow through the hERG ion channel. Using a collection of 1075 discovery compounds with hERG inhibition measured in our standard patch–clamp electrophysiology assay, molecular features important for drug-induced inhibition were identified using a combination of statistical inference algorithms and manual hypothesis generation and testing. While many of the features used in the model reflect those referenced in the literature, several aspects of the model provide new insight into the role of physicochemical properties, electrostatics, and novel pharmacophores in hERG inhibition. Coefficients for these 10 features were then determined by least median squares regression, resulting in a model with an R2 ∼ 0.66 and RMS error (RMSe) of 0.47 log units for an external test set. Significant additional validation performed using a large collection of subsequent discovery data has been very encouraging with an R2 = 0.54 and an RMSe of 0.63 log units. The performance of the model across several different chemotypes is demonstrated and discussed.

We describe the development and validation of an in silico model of hERG inhibition. The model includes several factors not previously reported for the estimation of hERG inhibition.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 18, 15 September 2007, Pages 6182–6192
نویسندگان
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