title: Estimation of hERG inhibition of drug candidates using multivariate property and pharmacophore SAR.
abstract: 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 R(2) approximately 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 R(2)=0.54 and an RMSe of 0.63 log units. The performance of the model across several different chemotypes is demonstrated and discussed.
authors.affiliation: Computer-Assisted Drug Design, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA. stephen.johnson@bms.com
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Hongwen
authors.initials: H
authors.lastname: Yue
authors.forename: Mary Lee
authors.initials: ML
authors.lastname: Conder
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.forename: Paul
authors.initials: P
authors.lastname: Levesque
mesh_terms: D003198:Computer Simulation; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D004364:Pharmaceutical Preparations