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Aug 1, 2009 (Vol. 29, No. 14)

Streamlining In Silico Compound Profiling

New Tools Have Applications in Drug Repurposing and Investigation of Off-Target Effects

  • Repurposing Drugs

    Click Image To Enlarge +
    Figure 1. The matrix profile generated from the search of astemizole-like compounds.

    Given the tremendous costs expended in drug development, organizations cannot afford to abandon investments outright. In silico profiling provides a low-cost opportunity to develop new strategies for failed candidates and currently marketed drugs, making it possible to capitalize on past work and enhance an overall drug portfolio.

    Recently scientists at a major pharmaceutical firm used in silico profiling to develop a novel hit series of small molecule somatostatin 5 receptor antagonists based on astemizole. If they had used AurPROFILER, a consensus profile would have been obtained through a similarity search (chemical similarity index range, 0.7–1) using astemizole as the seed structure. AurPROFILER would have found 21 similar molecules in the AurSCOPE knowledge database across 33 targets (10 more targets are associated with astemizole alone).

    When this consensus profile was expanded to show the full matrix, scientists would have seen an unexpected cluster of structures acting on somatostatin receptors (Figure 1).

    While the consensus profile performed indicated only micromolar activity at SST5, the presence of any activity at all on this target was interesting because somatostatin receptors differ significantly from the other receptor families targeted by the seed structure. This finding was enough to prompt optimization efforts, resulting in the development of a new potent, highly selective ligand for somatostatin receptor.



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