title: 3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines.
abstract: Mer kinase is a novel therapeutic target for many cancers, and overexpression of Mer receptor tyrosine kinase has been observed in several kinds of tumors. To deeply understand the structure-activity correlation of a series of pyridine/pyrimidine analogs as potent Mer inhibitors, a combined molecular docking and three-dimensional quantitative structure-activity relationship modeling was carried out. A comparative molecular similarity indices analysis model was developed based on the maximum common substructure alignment. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.599, and non-cross-validated r2 value was 0.984. Furthermore, the results of internal validation such as bootstrapping, Y-randomization as well as external validation (the external predictive correlation coefficient r2 ext = 0.728) confirmed the rationality and good predictive ability of the model. Using the crystal structure of Mer kinase, the selected pyridine/pyrimidine compounds were docked into the enzyme active site. Some key amino acid residues were determined, and hydrogen bonding and hydrophobic interactions between Mer kinase and inhibitors were identified. The satisfactory results from this study may aid in the research and development of novel potent Mer kinase inhibitors.
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao University, Qingdao, 266071, Shandong, China, zyu_01@126.com.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yu
authors.forename: Xianchao
authors.initials: X
authors.lastname: Li
authors.forename: Cuizhu
authors.initials: C
authors.lastname: Ge
authors.forename: Hongzong
authors.initials: H
authors.lastname: Si
authors.forename: Lianhua
authors.initials: L
authors.lastname: Cui
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Duan
authors.forename: Honglin
authors.initials: H
authors.lastname: Zhai
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011743:Pyrimidines; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase