Abdullahi Maryam, Olotu Fisayo A, Soliman Mahmoud E
Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South Africa.
Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban 4001, South Africa; College of Pharmacy and Pharmaceutical Sciences, Florida Agricultural and Mechanical University, FAMU, Tallahassee, FL 32307, USA.
Comput Biol Chem. 2018 Apr;73:49-56. doi: 10.1016/j.compbiolchem.2018.02.002. Epub 2018 Feb 5.
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.
淋巴细胞功能相关抗原-1（LFA-1）在炎症和自身免疫性疾病的病理生理学中起着重要作用。其活性和非活性构象分别与其患病和未患病状态相关。这取决于其在活性位点对其内在配体（ICAM）的亲和力程度以及α7螺旋处伴随的协同配位。这增强了抑制剂以变构方式破坏这种相互作用的作用。在此，我们首次利用分子动力学模拟描述了一种新型LFA-1拮抗剂Lifitegrast（SAR1118）与I结构域变构位点（IDAS）结合时的结构动力学，该动力学表征了其抑制作用。这项研究的结果表明，抑制剂稳定了闭合构象，并将开放构象转变为低ICAM亲和力状态（闭合），α7螺旋的向上移动以及活性位点的相应转变证明了这一点。在这两种情况下，都有利于形成非疾病非活性形式。通过变构调节，抑制剂显著恢复了蛋白质稳定性，增强了紧凑性并降低了残余波动，这对其在改善免疫和炎症性疾病中的效力至关重要，这与实验研究一致。因此，这些发现可作为探索变构结构域及其活性位点亲和力调节的基础，以帮助设计更具特异性和选择性的抑制剂。
