title: Quantitative structure-activity relationship study on BTK inhibitors by modified multivariate adaptive regression spline and CoMSIA methods.
abstract: Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell activation and development, and has emerged as a new molecular target for the treatment of autoimmune diseases and B-cell malignancies. In this study, two- and three-dimensional quantitative structure-activity relationship (2D and 3D-QSAR) analyses were performed on a series of pyridine and pyrimidine-based BTK inhibitors by means of genetic algorithm optimized multivariate adaptive regression spline (GA-MARS) and comparative molecular similarity index analysis (CoMSIA) methods. Here, we propose a modified MARS algorithm to develop 2D-QSAR models. The top ranked models showed satisfactory statistical results (2D-QSAR: Q(2) = 0.884, r(2) = 0.929, r(2)pred = 0.878; 3D-QSAR: q(2) = 0.616, r(2) = 0.987, r(2)pred = 0.905). Key descriptors selected by 2D-QSAR were in good agreement with the conclusions of 3D-QSAR, and the 3D-CoMSIA contour maps facilitated interpretation of the structure-activity relationship. A new molecular database was generated by molecular fragment replacement (MFR) and further evaluated with GA-MARS and CoMSIA prediction. Twenty-five pyridine and pyrimidine derivatives as novel potential BTK inhibitors were finally selected for further study. These results also demonstrated that our method can be a very efficient tool for the discovery of novel potent BTK inhibitors.
authors.affiliation: a Laboratory of Molecular Design and Drug Discovery, School of Basic Science , China Pharmaceutical University , Nanjing , Jiangsu , P.R. China.
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Ran
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: X
authors.initials: X
authors.lastname: Xiong
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.forename: T
authors.initials: T
authors.lastname: Lu
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000465:Algorithms; D062126:Databases, Chemical; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis
chemical_list: D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase
keywords: Bruton’s tyrosine kinase; CoMSIA; SAR; genetic algorithms; multivariate adaptive regression spline