title: Effective virtual screening strategy focusing on the identification of novel Bruton's tyrosine kinase inhibitors.
abstract: Dysregulation of the B-cell receptor (BCR) signaling pathway plays a vital role in the pathogenesis and development of B-cell malignancies. Bruton's tyrosine kinase (BTK), a key component in the BCR signaling, has been validated as a valuable target for the treatment of B-cell malignancies. In an attempt to find novel and potent BTK inhibitors, both ligand- and structure-based pharmacophore models were generated using Discovery Studio 2.5 and Ligandscout 3.11 with the aim of screening the ChemBridge database. The resulting hits were then subjected to sequential docking experiments using two independent docking programs, CDOCKER and Glide. Molecules displaying high glide scores and H-bond interactions with the key residue Met477 in both of the docking programs were retained. Drug-like criteria including Lipinski's rule of five and ADMET properties filters were employed for further refinement of the retrieved hits. By clustering, eight promising compounds with novel chemical scaffolds were finally selected and the top two ranking compounds were evaluated by molecular dynamics simulation. We believe that these compounds are of great potential in BTK inhibition and will be used for further investigation.
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, China.
authors.forename: Jianhu
authors.initials: J
authors.lastname: Xiao
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, China.
authors.forename: Shengping
authors.initials: S
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, China.
authors.forename: Minghao
authors.initials: M
authors.lastname: Luo
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, 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, 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, China. Electronic address: yslai@cpu.edu.cn.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification; D066264:Datasets as Topic; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: BTK inhibitor; Docking; Molecular dynamics.; Pharmacophore model; Virtual screening