Insights into phenylalanine derivatives recognition of VLA-4 integrin: From a pharmacophoric study to 3D-QSAR and molecular docking analyses
- Author(s)
- A Macchiarulo, Gabriele Costantino, Mirco Meniconi, Karin Pleban, Gerhard Ecker, Daniele Bellocchi, Roberto Pellicciari
- Abstract
The very late antigen-4 (VLA-4), also known as integrin a4ß1, 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: ß-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 avß3 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.
- Organisation(s)
- External organisation(s)
- Università degli Studi di Perugia, Medizinische Universität Wien
- Journal
- Journal of Chemical Information and Computer Sciences
- Volume
- 44
- Pages
- 1829-1839
- No. of pages
- 11
- ISSN
- 0095-2338
- Publication date
- 2004
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 3012 Pharmacy, Pharmacology, Toxicology
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/a559f60d-3694-488d-a406-225d1e36d5e9