A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists

Author(s): Yuwei Wang, Fang Bai, Hong Cao, Jiazhong Li, Huanxiang Liu, Paola Gramatica.

Journal Name: Combinatorial Chemistry & High Throughput Screening

Volume 18 , Issue 9 , 2015

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Abstract:

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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Article Details

VOLUME: 18
ISSUE: 9
Year: 2015
Page: [834 - 845]
Pages: 12
DOI: 10.2174/1386207318666150831125750
Price: $58

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