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À propos de : Insights into Phenylalanine Derivatives Recognition of VLA-4 Integrin: From aPharmacophoric Study to 3D-QSAR and Molecular Docking Analyses        

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  • Insights into Phenylalanine Derivatives Recognition of VLA-4 Integrin: From aPharmacophoric Study to 3D-QSAR and Molecular Docking Analyses
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  • The very late antigen-4 (VLA-4), also known as integrin α4β1, is expressed on monocytes, T- andB-lympohocytes, basophils, and eosinophils and is involved in the massive recruitment of granulocytes indifferent pathological conditions such as multiple sclerosis and asthma. VLA-4 interacts with its endogenousligand VCAM-1 during chronic inflammation, and blockade of VLA-4 /VCAM-1 interaction is a potentialtarget for immunosuppression. Two classes of VLA-4 antagonists have so far been reported: β-amino acidderivatives containing a diaryl urea moiety (BIO-1211) and phenylalanine derivatives (TR-14035). Withthe 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 constructedwith a restricted number of phenylalanine derivatives to identify the region of the protein that resemblessynthetic antagonists. The pharmacophore was instrumental in constructing an alignment of a set of 128compounds. 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 withthe pseudoreceptor surface. The 3D-QSAR analysis yielded a predictive model able to explain much of thevariance of the 128 antagonists. (iii) A homology modeling study of the headpiece of VLA-4 based on thecrystal structure of αvβ3 was performed. Docking experiments of TR-14035 into the binding site of VLA-4aided the interpretation of the 3D-QSAR model. The obtained results will be fruitful for the design of newpotent and selective antagonists of VLA-4.
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