3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists |
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Authors: | Singh Juswinder van Vlijmen Herman Lee Wen-Chemg Liao Yusheng Lin Ko-Chung Ateeq Humayun Cuervo Julio Zimmerman Craig Hammond Charles Karpusas Michael Palmer Rex Chattopadhyay Tapan Adams Steven P |
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Institution: | (1) Biogen Inc, 12 Cambridge Center, Cambridge, MA02142, USA;(2) Dept. of Crystallography, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, U.K |
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Abstract: | The integrin VLA-4 ( 4 1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2
CVof 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies. |
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Keywords: | 3D-QSAR COMFA VCAM-1 VLA-4 |
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