title: Structure-based discovery of novel 4,5,6-trisubstituted pyrimidines as potent covalent Bruton's tyrosine kinase inhibitors.
abstract: A series of novel 4,5,6-trisubstituted pyrimidines were designed as potent covalent Bruton's tyrosine kinase (BTK) inhibitors based on the structure of ibrutinib by using a ring-opening strategy. Among these derivatives, compound I1 exhibited the most potent inhibitory activity with an IC50 value of 0.07μM. The preliminary structure-activity relationship was discussed and the primary amino group at the C-4 position of pyrimidine was crucial for maintaining BTK activity. Furthermore, molecular dynamics simulations and binding free energy calculations were performed for three inhibitor-BTK complexes to determine the probable binding model, which provided a comprehensive guide for further structural modification and optimization.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jianhu
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yingyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Luo
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China. Electronic address: ding_ke@gibh.ac.cn.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: yslai@cpu.edu.cn.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D020134:Catalytic Domain; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine
keywords: BTK; Covalent kinase inhibitor; Molecular dynamics simulation; Pyrimidine; Structure–activity relationship