Research Article

Identification of Novel Neuroprotective Agents Using Pharmacophore Modeling

  1. Alan I. Faden1,
  2. Vilen A. Movsesyan1,
  3. Xueliang Fang2,
  4. Shaomeng Wang2

Article first published online: 23 NOV 2005

DOI: 10.1002/cbdv.200590127

Issue

Chemistry & Biodiversity

Chemistry & Biodiversity

Volume 2, Issue 11, pages 1564–1570, November 2005

Additional Information

How to Cite

Faden, Alan I., Movsesyan, Vilen A., Fang, X. and Wang, S. (2005), Identification of Novel Neuroprotective Agents Using Pharmacophore Modeling. Chemistry & Biodiversity, 2: 1564–1570. doi: 10.1002/cbdv.200590127

Author Information

  1. 1

    Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road. N. W., Research Building, Rm. EP12, Washington, DC 20057, USA (phone: +1-(202)-687-0492; fax: +1-(202)-687-0617)

  2. 2

    Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0934, USA

Publication History

  1. Issue published online: 23 NOV 2005
  2. Article first published online: 23 NOV 2005
  3. Manuscript Received: 4 APR 2005

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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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