3D-QSAR studies of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids as AKR1C3 inhibitors: Highlight the importance of molecular docking in conformation generation

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Abstract

AKR1C3 is a promising drug target for castration-resistant prostate cancer (CRPC). Here, 3D-QSAR analysis were performed on 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids to correlate their chemical structures with their observed AKR1C3 inhibitory activity. Three structural alignment methods employing various conformers were used to scrutinize the effect of conformation selection on the predictive accuracy of QSAR models. Using docked conformation, the best CoMFA and CoMSIA models were developed and validated with a training set of 61 molecules and a test set of 7 molecules. Detailed analysis of contour maps provided helpful structural insights to rational design of AKR1C3 inhibitors with enhanced potency.

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Acknowledgements

This work was supported by Natural Science Foundation of China (21572279, 81373258, 81522041, and 81602968), Natural Science Foundation of Guangdong Province (2014A020210009 and 2016A030313589), Medical Scientific Research Foundation of Guangdong Province (A2016201), Science Foundation of Guangzhou City (2014J4100165), and Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016). We also thank Special Program for Applied Research on Super Computation of

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