Rationalizing the activities of diverse cholecystokinin 2 receptor antagonists using molecular field points |
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Authors: | Low Caroline M R Vinter J G |
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Affiliation: | James Black Foundation, London, UK. c.low@imperial.ac.uk |
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Abstract: | Cholecystokinin 2 receptor antagonists encompass a wide range of structures. This makes them unsuitable candidates for existing 3D-QSAR methods and has led us to develop an alternative approach to account for their observed biological activities. A diverse set of 21 antagonists was subjected to a novel molecular field-based similarity analysis. The hypothesis is that compounds with similar field patterns will bind at the same target site regardless of their underlying structure. This initial report demonstrates a linear correlation between ligand similarity and biological activity for this challenging data set. A model generated with three molecules was used to predict the activity of 18 test compounds, with different chemotypes, with a root-mean-square error of 0.68 pKB units. The ability to automatically derive a molecular alignment without knowledge of the protein structure represents an improvement over existing pharmacophore methods and makes the method particularly suitable for scaffold-hopping. |
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