Fragment-based strategy for structural optimization in combination with 3D-QSAR

• DOI: 10.1007/s10822-013-9687-x
• Publication Date: 2013-10-31T05:37:32Z
• Authors: Haoliang Yuan; Wenting Tai; Shihe Hu; Haichun Liu; Yanmin Zhang; Sihui Yao; Ting Ran; Shuai Lu; Zhipeng Ke; Xiao Xiong; Jinxing Xu; Yadong Chen; Tao Lu
• Keywords: 0301 basic medicine; 0303 health sciences; c-Mer Tyrosine Kinase; Pyridines; Quantitative Structure-Activity Relationship; Receptor Protein-Tyrosine Kinases; Models, Theoretical; Benzocycloheptenes; Structure-Activity Relationship; 03 medical and health sciences; Catalytic Domain; Drug Design; Proto-Oncogene Proteins; Humans

Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure-activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets.