%0 Journal Article %1 bains:2004:PBMB %A Bains, William %A Basman, Antranig %A White, Cat %D 2004 %J Progress in Biophysics and Molecular Biology %K HERG, IKr, Molecular Prediction QSAR, algorithms, descriptors, genetic programming, %N 2 %P 205--233 %R doi:10.1016/j.pbiomolbio.2003.09.001 %T HERG binding specificity and binding site structure: Evidence from a fragment-based evolutionary computing SAR study %U http://www.sciencedirect.com/science/article/B6TBN-4BS4DJM-1/2/2bd8833742e401378469ee988d571705 %V 86 %X We describe the application of genetic programming, an evolutionary computing method, to predicting whether small molecules will block the HERG cardiac potassium channel. Models based on a molecular fragment-based descriptor set achieve an accuracy of 85-90% in predicting whether the IC50 of a 'blind' set of compounds is <1 muM. Analysis of the models provides a 'meta-SAR', which predicts a pharmacophore of two hydrophobic features, one preferably aromatic and one preferably nitrogen-containing, with a protonatable nitrogen asymmetrically situated between them. Our experience of the approach suggests that it is robust, and requires limited scientist input to generate valuable predictive results and structural understanding of the target.

@article{bains:2004:PBMB, abstract = {We describe the application of genetic programming, an evolutionary computing method, to predicting whether small molecules will block the HERG cardiac potassium channel. Models based on a molecular fragment-based descriptor set achieve an accuracy of 85-90% in predicting whether the IC50 of a 'blind' set of compounds is <1 [mu]M. Analysis of the models provides a 'meta-SAR', which predicts a pharmacophore of two hydrophobic features, one preferably aromatic and one preferably nitrogen-containing, with a protonatable nitrogen asymmetrically situated between them. Our experience of the approach suggests that it is robust, and requires limited scientist input to generate valuable predictive results and structural understanding of the target.}, added-at = {2008-06-19T17:35:00.000+0200}, author = {Bains, William and Basman, Antranig and White, Cat}, biburl = {https://www.bibsonomy.org/bibtex/2d0093dc63cd554c66ac7a2e542c9ce48/brazovayeye}, doi = {doi:10.1016/j.pbiomolbio.2003.09.001}, interhash = {1664817058279cdf31741d09bb6090dc}, intrahash = {d0093dc63cd554c66ac7a2e542c9ce48}, journal = {Progress in Biophysics and Molecular Biology}, keywords = {HERG, IKr, Molecular Prediction QSAR, algorithms, descriptors, genetic programming,}, month = {October}, notes = {Amedis, lilgp, Fixed weighted sum of ROC and Akaike fitness criterion (AIC) Many descriptors including not only description of compound but who and how measurements were made. GP run many times (1028+). http://www.elsevier.com/wps/find/journaldescription.cws_home/408/description#description Amedis Pharmaceuticals, Unit 162 Cambridge Science Park, Milton Road, Cambridge, UK p206 {"}...Fatal cardiac arrhythmias...{"} {"}HERG binds to many compounds.{"} {"}Testing for HERG...effectively mandatory...{"} p207/p221 empirically derived penalty for {"}over-complex models, in order to prevent over-fitting{"} p211 {"}GP can select efficiently from a large number of input variables{"}. p215 big difference between Training and validation ROC. Extracting chemically meaningful reasoning from evolved solutions. Relationship with possible mechanisms in HERG gap in cell wall. p226 {"}we belive it is efficient use of the machine{"} [ie computer time].}, number = 2, owner = {wlangdon}, pages = {205--233}, size = {29 pages}, timestamp = {2008-06-19T17:36:07.000+0200}, title = {{HERG} binding specificity and binding site structure: Evidence from a fragment-based evolutionary computing {SAR} study}, url = {http://www.sciencedirect.com/science/article/B6TBN-4BS4DJM-1/2/2bd8833742e401378469ee988d571705}, volume = 86, year = 2004 }