| Autor: |
Macchiarulo, Antonio, Costantino, Gabriele, Meniconi, Mirco, Pleban, Karin, Ecker, Gerhard, Bellocchi, Daniele, Pellicciari, Roberto |
| Zdroj: |
Journal of Chemical Information and Modeling; September 2004, Vol. 44 Issue: 5 p1829-1839, 11p |
| Abstrakt: |
The very late antigen-4 (VLA-4), also known as integrin 41, is expressed on monocytes, T- and B-lympohocytes, basophils, and eosinophils and is involved in the massive recruitment of granulocytes in different pathological conditions such as multiple sclerosis and asthma. VLA-4 interacts with its endogenous ligand VCAM-1 during chronic inflammation, and blockade of VLA-4 /VCAM-1 interaction is a potential target for immunosuppression. Two classes of VLA-4 antagonists have so far been reported: -amino acid derivatives containing a diaryl urea moiety (BIO-1211) and phenylalanine derivatives (TR-14035). With the aim of clarifying the structural basis responsible for VLA-4 recognition by phenylalanine derivatives, we developed a combined computational study on a set of 128 antagonists available through the literature. Our computational approach is composed of three parts. (i) A VCAM-1 based pharmacophore was constructed with a restricted number of phenylalanine derivatives to identify the region of the protein that resembles synthetic antagonists. The pharmacophore was instrumental in constructing an alignment of a set of 128 compounds. This alignment was exploited to build a pseudoreceptor model with the RECEPTOR program. (ii) 3D-QSAR analysis was carried out on the computed electrostatic and steric interaction energies with the pseudoreceptor surface. The 3D-QSAR analysis yielded a predictive model able to explain much of the variance of the 128 antagonists. (iii) A homology modeling study of the headpiece of VLA-4 based on the crystal structure of v3 was performed. Docking experiments of TR-14035 into the binding site of VLA-4 aided the interpretation of the 3D-QSAR model. The obtained results will be fruitful for the design of new potent and selective antagonists of VLA-4. |
| Databáze: |
Supplemental Index |
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