Idiopathic pulmonary fibrosis (IPF), a chronic disease characterised by progressive scarring of the lungs, has a survival rate of two to four years upon diagnosis. With increasing incidences of IPF each year, the urgent need for new treatment motivates research into antagonists of the RGD binding integrin, αVβ6, a protein linked to the initiation and progression of IPF. All-atom molecular dynamics (MD) simulations provide an understanding of how the dynamic changes of active site residues in αVβ6 contribute to ligand binding. In order to perform MD simulations using the CHARMM force field, parameters for new atom types have been developed and validated by comparison with target data calculated at the MP2/6-31G* level. MD simulations of αVβ6 in complex with its natural ligand, pro-TGF-β1, show a bidentate ArgLig-AspRec interaction that is maintained throughout dynamics. An interaction between AspLig and a Mg2+ ion in the β6 subunit is also conserved. Our interest focuses on how these interactions compare with those of a RGD mimetic. This mimetic has served as a framework for a series of potential αVβ6 antagonists. We have investigated the persistence of interactions compared with the potency of analogues based on a scaffold containing 1,4-tetrahydro naphthyridine, a carboxyl and an aryl group.

Molecular simulation to accelerate discovery of αVβ6 integrin inhibitors

2019 Fall National Meeting

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