Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical
trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although
initially effective, the drug resistance problem will emerge eventually, which results in a high medical
need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel
AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives
and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D
MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated,
demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and
CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities,
which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically
useful for rational design and screening of promising chemicals with high antiandrogenic activities.
Keywords: Androgen receptor (AR), comparative molecular field analysis (CoMFA), prostate cancer (PCa), comparative
molecular similarity indices analysis (CoMSIA), multiple linear regression (MLR).
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