title: Novel strategy for three-dimensional fragment-based lead discovery.
abstract: Fragment-based drug design (FBDD) is considered a promising approach in lead discovery. However, for a practical application of this approach, problems remain to be solved. Hence, a novel practical strategy for three-dimensional lead discovery is presented in this work. Diverse fragments with spatial positions and orientations retained in separately adjacent regions were generated by deconstructing well-aligned known inhibitors in the same target active site. These three-dimensional fragments retained their original binding modes in the process of new molecule construction by fragment linking and merging. Root-mean-square deviation (rmsd) values were used to evaluate the conformational changes of the component fragments in the final compounds and to identify the potential leads as the main criteria. Furthermore, the successful validation of our strategy is presented on the basis of two relevant tumor targets (CDK2 and c-Met), demonstrating the potential of our strategy to facilitate lead discovery against some drug targets.
authors: Laboratory of Molecular Design and Drug Discovery, School of Basic Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors: Haoliang
authors: H
authors: Yuan
authors: Tao
authors: T
authors: Lu
authors: Ting
authors: T
authors: Ran
authors: Haichun
authors: H
authors: Liu
authors: Shuai
authors: S
authors: Lu
authors: Wenting
authors: W
authors: Tai
authors: Ying
authors: Y
authors: Leng
authors: Weiwei
authors: W
authors: Zhang
authors: Jian
authors: J
authors: Wang
authors: Yadong
authors: Y
authors: Chen
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D016208:Databases, Factual; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries; D019859:Proto-Oncogene Proteins c-met; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2