Computational Models for Predicting the Binding Affinities of Ligands for the Wild-Type Androgen Receptor and a Mutated Variant Associated with Human Prostate Cancer
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- 作者：Ni Ai ; Robert K. DeLisle ; Seong Jae Yu ; and William J. Welsh
- 刊名：Chemical Research in Toxicology
- 出版年：2003
- 出版时间：December 2003
- 年：2003
- 卷：16
- 期：12
- 页码：1652 - 1660
- 全文大小：127K
- 年卷期：v.16,no.12(December 2003)
- ISSN：1520-5010
文摘
In the present study, values of the binding energy (BE) were calculated for the rat androgenreceptor on a data set of 25 steroidal and nonsteroidal compounds for which published valuesof the observed binding affinity (Ki) are available. A correlation between BE and pKi was evident(r2 = 0.50) for the entire data set and became more pronounced when the steroids andnonsteroids were plotted separately (r2 
f"> 0.76). Including BE as an additional descriptor tosupplement the default steric-electrostatic descriptors in comparative molecular field analysisdramatically improved the predictive ability of the resulting three-dimensional quantitativestructure-activity relationship models. We also demonstrate that the observed loss in ligandspecificity 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, 17
fchars/beta2.gif" BORDER=0 ALIGN="middle">-estradiol, progesterone, and 17fchars/alpha.gif" BORDER=0>-hydroxyprogesterone.
f"> 0.76). Including BE as an additional descriptor tosupplement the default steric-electrostatic descriptors in comparative molecular field analysisdramatically improved the predictive ability of the resulting three-dimensional quantitativestructure-activity relationship models. We also demonstrate that the observed loss in ligandspecificity 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, 17fchars/beta2.gif" BORDER=0 ALIGN="middle">-estradiol, progesterone, and 17fchars/alpha.gif" BORDER=0>-hydroxyprogesterone.