title: 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.
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.
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Deyan
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Infinitus (China) Co. Ltd, Guangzhou 510663, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: luohb77@mail.sysu.edu.cn.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship
chemical_list: C000608288:3,4-dihydroisoquinolin-1(2H)-one; D001565:Benzoates; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3
keywords: 3D-QSAR; AKR1C3 inhibitors; Benzoic acids; Dihydroisoquinoline; Docking