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Prediction of Small‐Molecule Binding to Cytochrome P450 3A4: Flexible Docking Combined with Multidimensional QSAR
Author(s) -
Lill Markus A.,
Dobler Max,
Vedani Angelo
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500024
Subject(s) - quantitative structure–activity relationship , docking (animal) , chemistry , drug discovery , molecule , hydrogen bond , computational chemistry , molecular dynamics , stereochemistry , computational biology , biological system , biology , biochemistry , medicine , nursing , organic chemistry
The inhibition of cytochrome P450 3A4 (CYP3A4) by small molecules is a major mechanism associated with undesired drug–drug interactions, which are responsible for a substantial number of late‐stage failures in the pharmaceutical drug‐development process. For a quantitative prediction of associated pharmacokinetic parameters, a computational model was developed that allows prediction of the inhibitory potential of 48 structurally diverse molecules. Based on the experimental structure of CYP3A4, possible binding modes were first sampled by using automated docking (Yeti software) taking protein flexibility into account. The results are consistent with both X‐ray crystallographic data and data from metabolic studies. Next, an ensemble of energetically favorable orientations was composed into a 4D dataset for use as input for a multidimensional QSAR technique (Raptor software). A dual‐shell binding‐site model that allows an explicit induced fit was then generated by using hydrophobicity scoring and hydrogen‐bond propensity. The simulation reached a cross‐validated r 2 value of 0.825 and a predictive r 2 value of 0.659. On average, the predicted binding affinity of the training ligands deviates by a factor of 2.7 from the experiment; those of the test set deviate by a factor of 3.8 in K i .