HERG binding specificity and binding site structure: Evidence from a fragment-based evolutionary computing SAR study

Created by W.Langdon from gp-bibliography.bib Revision:1.4420

  author =       "William Bains and Antranig Basman and Cat White",
  title =        "{HERG} binding specificity and binding site structure:
                 Evidence from a fragment-based evolutionary computing
                 {SAR} study",
  journal =      "Progress in Biophysics and Molecular Biology",
  year =         "2004",
  volume =       "86",
  pages =        "205--233",
  number =       "2",
  month =        oct,
  keywords =     "genetic algorithms, genetic programming, HERG, IKr,
                 QSAR, Molecular descriptors, Prediction",
  DOI =          "doi:10.1016/j.pbiomolbio.2003.09.001",
  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.",
  owner =        "wlangdon",
  URL =          "http://www.sciencedirect.com/science/article/B6TBN-4BS4DJM-1/2/2bd8833742e401378469ee988d571705",
  size =         "29 pages",
  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+).

                 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].",

Genetic Programming entries for William Bains Antranig Basman Cat White