Identification of potent and novel α4β1 antagonists using in silico screening

Juswinder Singh, William M. Abraham, Steven P. Adams, Herman Van Vlijmen, Yusheng Liao, Wen Cherng Lee, Mark Cornebise, Mary Harris, I. Hsiang Shu, Alan Gill, Julio H. Cuervo

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Abstract

The antigen α4β1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of α4β1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based α4β1 inhibitor (1; 4-[N′-(2-methylphenyl)-ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to α4β1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit α4β1 association with VCAM-1, with the most potent compound having an [C50 of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these α4β1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists. This approach should be useful in identification of nonpeptidic α4β1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts.

Original languageEnglish (US)
Pages (from-to)2988-2993
Number of pages6
JournalJournal of Medicinal Chemistry
Volume45
Issue number14
DOIs
StatePublished - Jul 4 2002

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Singh, J., Abraham, W. M., Adams, S. P., Van Vlijmen, H., Liao, Y., Lee, W. C., Cornebise, M., Harris, M., Shu, I. H., Gill, A., & Cuervo, J. H. (2002). Identification of potent and novel α4β1 antagonists using in silico screening. Journal of Medicinal Chemistry, 45(14), 2988-2993. https://doi.org/10.1021/jm020054e