Abstract
The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pro-TGF-β1, show the persistence over time of a bidentate Arg-Asp ligand-receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg2+ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential αvβ6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-π interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol-1, on average, of experiments.
Highlights
Integrin αvβ[6] is a transmembrane, heterodimeric protein
Understanding which structural features of the inhibitor are most important for driving affinity from molecular simulations complements the empirical process that is generally used in integrin lead optimisation where compounds are made, tested and structure activity relationships (SAR) are developed
In order to compare the results of the free energy perturbation (FEP) simulations with simpler methods, we investigate the relationship between docking scores and experimental activity (Table 3)
Summary
Integrin αvβ[6] is a transmembrane, heterodimeric protein. The involvement of integrins in the progression of several tumour types and diseases including idiopathic pulmonary fibrosis (IPF)makes them important targets for the development of new drug compounds. 1–3 IPF is a chronic disease characterised by progressive scarring of the lungs. 4 The involvement of αvβ[6] in the initiation and progression of IPF motivates research to understand the conformational changes and binding properties of αvβ[6] with its natural ligand, the pro-domain of TGF-β1, and a series of potential antagonists. 6,7 A drug antagonist of αvβ[6] could treat IPF through active site binding in place of TGF-β1. Predicting ligand affinity in integrin drug discovery from docking studies has historically been difficult ( it is generally possible to rationalise the activity once the data is available 8 ). Understanding which structural features of the inhibitor are most important for driving affinity from molecular simulations complements the empirical process that is generally used in integrin lead optimisation where compounds are made, tested and structure activity relationships (SAR) are developed. Computational predictions become important with longer syntheses, which use considerable resources and take months to complete
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