Three-dimensional quantitative structure-activity relationship analysis for human pregnane X receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.
The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process.
School of Pharmacy, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan; Research Laboratories, Toyama Chemical Company, Ltd., Toyama, 930-8508, Japan.
Koichi
K
Handa
Izumi
I
Nakagome
Noriyuki
N
Yamaotsu
Hiroaki
H
Gouda
Shuichi
S
Hirono
D001185:Artificial Intelligence; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D030562:Databases, Protein; D055808:Drug Discovery / Q000379:methods*; D004735:Energy Transfer; D004790:Enzyme Induction / Q000187:drug effects; D005103:Expert Systems; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000077297:Pregnane X Receptor; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011987:Receptors, Steroid / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results
D065701:Cytochrome P-450 CYP3A Inducers; D008024:Ligands; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A
QSAR; computational ADME; molecular modeling; protein structure; structure activity relationship (SAR)