Allosteric inhibition abrogates dysregulated LFA-1 activation: Structural insight into mechanisms of diminished immunologic disease |
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| Affiliation: | 1. Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South Africa;2. College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, FL 32307, USA;1. Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland;2. Warsaw University, Faculty of Chemistry, Pasteura 1, 02-093 Warsaw, Poland;1. Department of Chemistry, Periyar Arts College, Cuddalore 607 001, Tamilnadu, India;2. Department of Chemistry, Annamalai University, Annamalainagar 608 002, Tamilnadu, India;1. Danish Research Institute of Translational Neuroscience - DANDRITE, Nordic-EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark;2. Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia;1. Anadolu University, Science Faculty, Department of Physics, 26470, Eskişehir, Turkey;2. Eskişehir Osmangazi University, Art and Sciences Faculty, Department of Physics, Eskişehir, Turkey;3. Eskişehir Osmangazi University, Central Research Laboratory, Application and Research Centre, Eskişehir, Turkey |
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| Abstract: | Lymphocyte Function Associated antigen-1(LFA-1) has been implicated severely in the pathophysiology of inflammatory and autoimmune diseases. Its active and inactive conformations correlate with its diseased and non-diseased state respectively. This is determined by its degree of affinity for its intrinsic ligand (ICAM) at the active site and accompanying synergistic coordination at the α7 helix. This potentiates the role of inhibitors in disrupting this interaction allosterically. Herein, we present a first account of the structural dynamics which characterizes the inhibitory effect of a novel LFA-1 antagonist, Lifitegrast (SAR1118), upon binding to the I-domain allosteric site (IDAS) using molecular dynamics simulation. Findings from this study revealed that the inhibitor stabilized the closed conformation and reversed the open conformation to a low ICAM-affinity state (closed) as evidenced by the upward movement of the α7 helix and corresponding transitions at the active site. This in both cases favors the formation of the non-disease inactive form. Upon allosteric modulation, the inhibitor significantly restored protein stability, enhanced compactness and decreased residual fluctuation as crucial to its potency in the amelioration of immunological and inflammatory diseases which agrees with experimental studies. These findings could therefore serve as the basis for the exploration of the allosteric domain and its active site affinity modulation to aid the design of more specific and selective inhibitors. |
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| Keywords: | Affinity Allosteric Antagonist Immunologic Lifitegrast LFA-1 |
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