Discovery of small molecule inhibitors of adenovirus by disrupting E3-19K/HLA-A2 interactions

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Ren, Jinhong¹  Dsouza, Nikita R.²  Deng, Hui³  Lee, Hyun^1,4,5  Bouvier, Marlene³  Johnson, Michael E.^1,2,4 

[1] Univ Illinois, Ctr Biomol Sci, 900 S Ashland Ave, Chicago, IL 60607 USA

[2] Univ Illinois, Dept Bioengn, 835 S Wolcott Ave, Chicago, IL 60612 USA

[3] Univ Illinois, Dept Microbiol & Immunol, 835 S Wolcott Ave, Chicago, IL 60612 USA

[4] Univ Illinois, Dept Med Chem & Pharmacognosy, 900 S Ashland Ave, Chicago, IL 60607 USA

[5] Univ Illinois, Biophys Core, Res Resources Ctr, 900 S Ashland Ave, Chicago, IL 60607 USA

关键词: Adenovirus;    E3-19K;    HLA-A2;    Protein-protein interactions;    Small molecule inhibitors;    Molecular dynamic simulations;    Molecular mechanics/generalized-born surface area (MM/GBSA);    Computational solvent mapping;    Virtual screening;    Surface plasmon resonance;   

DOI  :  10.1016/j.bmcl.2018.07.036

来源: Elsevier

【 摘 要 】

The binding of the adenovirus (Ad) protein E3-19K with the human leukocyte antigen (HLA) plays an important role in Ad infections, which is the causative agent of a series of gastrointestinal, respiratory and ocular diseases. The objective of this research is to evaluate the essential interactions between E3-19K and HLA-A2 using the X-ray crystal structure of the E3-19K/HLA-A2 complex, and to identify small molecules that could potentially disrupt their binding. Computational methods, including molecular dynamic simulations, MM/GBSA calculations, and computational solvent mapping, were implemented to determine potential binding site(s) for small molecules. The previous experimentally determined hot spot residues, Q54 and E177 in HLA-A2, were also predicted to be the dominant residues for binding to E3-19K by our theoretical calculations. Several other residues were also found to play pivotal roles for the binding of E3-19K with HLA-A2. Residues adjacent to E177, including Q54 and several other residues theoretically predicted to be crucial in HLA-A2 were selected as a potential binding pocket to perform virtual screening with 1200 compounds from the Prestwick library. Seven hits were validated by surface plasmon resonance (SPR) as binders to HLA-A2 as a first step in identifying molecules that can perturb its association with the Ad E3-19K protein.

【 授权许可】

Free