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

0301 basic medicine 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
DOI: 10.1007/s10822-013-9687-x Publication Date: 2013-10-31T05:37:32Z
ABSTRACT
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (38)
CITATIONS (12)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....