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Identification of Novel Neuroprotective Agents Using Pharmacophore Modeling
Author(s) -
Faden Alan I.,
Movsesyan Vilen A.,
Fang Xueliang,
Wang Shaomeng
Publication year - 2005
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200590127
Subject(s) - pharmacophore , neuroprotection , chemistry , computational biology , pharmacology , combinatorial chemistry , stereochemistry , biology
In addition to its endocrine function, for which it was named, thyrotropin‐releasing hormone (TRH) has substantial neuroprotective actions as well as other physiological effects. We have developed a number of modified TRH analogues as well as cyclic dipeptides structurally related to a major metabolic product of TRH, which have enhanced neuroprotective activity but none of the other major physiological effects of TRH. The extensive structure–activity data developed with these compounds were used to develop a pharmacophore model. Subsequently, a web‐based pharmacophore searching program was used to query several large three‐dimensional databases. Of the 219 compounds identified whose structures met the pharmacophore model, 15 were chosen for study in a classical model of neuronal cell death in vitro; five of these, 2 – 6 , showed neuroprotective activity. Thus, pharmacophore modeling developed from neuroprotective small peptides can be used to identify novel lead compounds as neuroprotective agents.