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Development of Tools for the Design of Selectin Antagonists
Author(s) -
Kolb Hartmuth C.,
Ernst Beat
Publication year - 1997
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.19970031006
Subject(s) - pharmacophore , antagonist , rational design , docking (animal) , chemistry , stereochemistry , receptor , biochemistry , nanotechnology , materials science , medicine , nursing
Abstract A molecular modeling tool for the rational design of E‐selectin antagonists based on the lead structure sialyl Lewis x has been developed. The binding affinity to the receptor is considerably influenced by the entropy and consequently by the antagonist's ability to place its pharmacophores in an optimal spatial arrangement, i.e., by its preorganization for binding. The computational model assesses the preorganization of a potential selectin antagonist with the aid of Monte Carlo (jumping between wells)/stochastic dynamics [MC(JBW)/SD] simulations. The model has been validated by correlating preorganization and bioactivity of several selectin antagonists. The results suggest that only preorganized compounds are likely to bind to E‐selectin.