PLAUSIBLE BINDING MODE OF THE ACTIVE Α4β1 ANTAGONIST, MK-0617, DETERMINED BY DOCKING AND FREE ENERGY CALCULATIONS

Abstract

In the last years, the development of small molecule antagonists of VLA-4 for the treatment of diseases, where cell trafficking and activation are important, has increased considerably. Among them, the MK-0617 ligand has proven to be a highly potent and orally active α4β1 antagonist. However, the binding mode of this ligand in the integrin binding site remains unknown. Herein we report a thermodynamic analysis of the interaction between MK-0617 (and one of its isomers) and the VLA-4 protein using molecular docking and the free energy perturbation calculations, based on a comparative model of the α4β1 receptor. Initial complex coordinates were taken from molecular docking assays and submitted to alchemical transformations. Free energy of binding ΔΔG values, derived from experimental IC50 values, were taken as a parameter for determining the most likely binding mode. In addition, molecular dynamics simulations of these ligands within the α4β1 binding site were carried out to elucidate the binding energy profile and identify the most significant residues. Our results indicate that MK-0617 fits within the binding site in a stretched conformation, pointing the carboxylate group towards the MIDAS ion. We observe that, despite the fact that the main contribution to the energetic binding process is due to the electrostatic ion contribution, the nonpolar contribution is not negligible. Additionally, a network of hydrogen bonds participate in stabilizing the ligand-receptor interaction.

Integrin Ligands with α/β‐Hybrid Peptide Structure: Design, Bioactivity, and Conformational Aspects

“…In the diastereoisomer 50 the PhCO‐Asp group is positioned at the opposite side of the Amo ring with respect to 49 , and the central dihedral angle θ of Amo adopts a –g conformation (due to the opposite stereochemistry, – g and + g of in ( R )‐Amo and ( S )‐Amo, respectively, correspond). In essence, the Amo scaffold of 49 imposes a preferential conformation, that is compatible with the 3D models (see Section ) reported in the literature for BIO1211 41 and similar compounds.…”

“…As for the other integrins, models of α5β1 integrin were initially developed by homology on the basis of the αvβ3 integrin‐ 3 complex structure, or by binding pocket mapping, and were subsequently utilized to perform molecular docking simulations to rationalize the structural requisites of ligand‐receptor binding. In a similar way, homology models or models derived from a combination of theoretical methods were utilized to design potential ligands of integrin α4β1. Currently, high‐resolution structural data are also available for the ectodomains of the integrin αIIbβ3 54,55 and of the integrin α5β1 56 in complexes with their respective RGD ligands.…”

“…The structures of the novel peptidomimetics were designed on the basis of the models developed by 3D‐QSAR analysis of large libraries of compounds containing diphenylureas . This approach led to the retro sequences BnCO‐Asp‐β 2 ‐Pro‐AMPUMP 43 , and BnCO‐ iso Asp‐β 2 ‐Pro‐AMPUMP 44 (Fig.…”

5‐aminomethyloxazolidine‐2,4‐dione hybrid α/β‐dipeptide scaffolds as inductors of constrained conformations: Applications to the synthesis of integrin antagonists

“…Figure shows also a comparison of the representative structures of 6 and 7 calculated by ROESY and restrained molecular dynamics, with the bioactive geometries of the compounds 1 , 2 , and 3 as reported in the literature, representative of the 3D models developed by 3D QSAR or molecular docking . Both 6 and 7 tend to adopt similar semi ‐bent conformations; however, the relative display of the diphenylurea, the carboxylate group, and the aromatic group, imposed by the ( S )‐Amo‐urea rigid scaffold of the antagonist 6 , seems to reproduce the geometries of the pharmacophores of reference compounds more closely, accounting for the comparatively higher efficacy to inhibit Jurkat cells adhesion to VCAM‐1 (Table ).…”

“…The significant biological activity of the structurally correlated PhCO‐( S )‐Asp(OH)‐( S )‐Amo‐APUMP ( 6 ) and PhCO‐( S )‐Asp(OH)‐( R )‐Amo‐APUMP ( 7 ) prompted us to analyze the in‐solution conformations by NMR spectroscopy and MD simulations, to check the coherence with the 3D geometric requisites of the models reported in the literature for α4β1 antagonists , . Molecular conformations were investigated by 2D ROESY in 8:2 [D6]DMSO/H 2 O; [D6]DMSO alone or mixtures of [D6]DMSO and H 2 O have been recommended by several authors as excellent biomimetic media.…”