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Computational models for predicting the binding affinities of ligands for the wild-type androgen receptor and a mutated variant associated with human prostate cancer
- Source :
- Chemical research in toxicology. 16(12)
- Publication Year :
- 2003
-
Abstract
- In the present study, values of the binding energy (BE) were calculated for the rat androgen receptor on a data set of 25 steroidal and nonsteroidal compounds for which published values of the observed binding affinity (K(i)) are available. A correlation between BE and pK(i) was evident (r(2) = 0.50) for the entire data set and became more pronounced when the steroids and nonsteroids were plotted separately (r(2) congruent with 0.76). Including BE as an additional descriptor to supplement the default steric-electrostatic descriptors in comparative molecular field analysis dramatically improved the predictive ability of the resulting three-dimensional quantitative structure-activity relationship models. We also demonstrate that the observed loss in ligand specificity between the wild-type (wt) AR and the T877A mutant AR associated with androgen-independent prostate cancer is reflected in decreased BE values (i.e., higher binding affinity) for the antiandrogen pharmaceutical hydroxyflutamide and for several nonandrogenic endogenous steroids, most notably cortisol, corticosterone, 17beta-estradiol, progesterone, and 17alpha-hydroxyprogesterone.
- Subjects :
- Male
medicine.medical_specialty
medicine.drug_class
Quantitative Structure-Activity Relationship
Plasma protein binding
Toxicology
Antiandrogen
Ligands
Models, Biological
Prostate cancer
chemistry.chemical_compound
Internal medicine
medicine
Animals
Humans
Receptor
Wild type
Prostatic Neoplasms
General Medicine
medicine.disease
Ligand (biochemistry)
Rats
Androgen receptor
Kinetics
Endocrinology
chemistry
Amino Acid Substitution
Models, Chemical
Receptors, Androgen
Thermodynamics
Hydroxyflutamide
Protein Binding
Subjects
Details
- ISSN :
- 0893228X
- Volume :
- 16
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Chemical research in toxicology
- Accession number :
- edsair.doi.dedup.....e3b38ab1ea30918fb52b6e7952ae87ae