Identification of novel neuroprotective agents using pharmacophore modeling |
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Authors: | Faden Alan I Movsesyan Vilen A Fang Xueliang Wang Shaomeng |
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Affiliation: | Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road. N. W., Research Building, Rm. EP12, Washington, DC 20057, USA. fadena@georgetown.edu |
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Abstract: | 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. |
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