title: Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches.
abstract: In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R²(train) = 0.935, R²(test) = 0.902, Q²(LOO) = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC(-)), oprea's lead-like (opr_leadlike), subdivided van der Waal's surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R²(train) = 0.944, R²(test) = 0.892, Q²(LOO) = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity.
authors.affiliation: College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. chenmeimei1984@163.com.
authors.forename: Meimei
authors.initials: M
authors.lastname: Chen
authors.affiliation: College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. mei_tcm@163.com.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. keerer1990@163.com.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Lai
authors.affiliation: College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. meinuohua2007@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Kang
authors.affiliation: College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China. ghjzyz@163.com.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Gan
authors.affiliation: College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China. gaoxingchem@xmu.edu.cn.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Gao
mesh_terms: D015195:Drug Design; D006801:Humans; D016014:Linear Models; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D062367:ortho-Aminobenzoates; D000099150:Receptor, Farnesoid X-Activated; C031385:anthranilic acid
keywords: FXR; QSAR; anthranilic acid derivatives; docking