Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein

被引:1
|
作者
Romero, Atilio Reyes [1 ,2 ]
Kubica, Katarzyna [1 ]
Kitel, Radoslaw [1 ]
Rodriguez, Ismael [1 ]
Magiera-Mularz, Katarzyna [1 ]
Domling, Alexander [2 ]
Holak, Tad A. [1 ]
Surmiak, Ewa [1 ]
机构
[1] Jagiellonian Univ, Fac Chem, Dept Organ Chem, Gronostajowa 2, PL-30387 Krakow, Poland
[2] Univ Groningen, Dept Drug Design, A Deusinglaan 1, NL-9713 AV Groningen, Netherlands
来源
MOLECULES | 2022年 / 27卷 / 23期
关键词
protein-protein interactions; anti-cancer therapy; nuclear magnetic resonance; protein-peptide docking; small-molecule inhibitors; DRUG DISCOVERY; UBL5; GENE; UBIQUITIN; DOCKING; RECOGNITION; PEPTIDES; BINDING;
D O I
10.3390/molecules27238282
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein.
引用
收藏
页数:15
相关论文
共 50 条
  • [41] Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors
    Hei, Yuan -Yuan
    Wang, Si
    Xi, Xiao-Xiao
    Wang, Hai-Peng
    Guo, Yuanxu
    Xin, Minhang
    Jiang, Congshan
    Lu, Shemin
    Zhang, San-Qi
    JOURNAL OF PHARMACEUTICAL ANALYSIS, 2022, 12 (04) : 653 - 663
  • [42] Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase
    McIntire, Laura Beth J.
    Lee, Kyu-In
    Chang-Ileto, Belle
    Di Paolo, Gilbert
    Kim, Tae-Wan
    JOURNAL OF BIOMOLECULAR SCREENING, 2014, 19 (04) : 585 - 594
  • [43] Design of small-molecule thrombin inhibitors based on the cis-5-phenylproline scaffold
    K. V. Kudryavtsev
    D. A. Shulga
    V. I. Chupakhin
    A. V. Churakov
    N. G. Datsuk
    D. V. Zabolotnev
    N. S. Zefirov
    Russian Chemical Bulletin, 2011, 60 : 685 - 693
  • [44] Small-Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1a
    Buckley, Dennis L.
    Gustafson, Jeffrey L.
    Van Molle, Inge
    Roth, Anke G.
    Tae, Hyun Seop
    Gareiss, Peter C.
    Jorgensen, William L.
    Ciulli, Alessio
    Crews, Craig M.
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2012, 51 (46) : 11463 - 11467
  • [45] Small-Molecule Inhibitors of AF6 PDZ-Mediated Protein-Protein Interactions
    Vargas, Carolyn
    Radziwill, Gerald
    Krause, Gerd
    Diehl, Anne
    Keller, Sandro
    Kamdem, Nestor
    Czekelius, Constantin
    Kreuchwig, Annika
    Schmieder, Peter
    Doyle, Declan
    Moelling, Karin
    Hagen, Volker
    Schade, Markus
    Oschkinat, Hartmut
    CHEMMEDCHEM, 2014, 9 (07) : 1458 - 1462
  • [46] Computer-Aided Discovery of Small Molecule Inhibitors of Thymocyte Selection-Associated High Mobility Group Box Protein (TOX) as Potential Therapeutics for Cutaneous T-Cell Lymphomas
    Agrawal, Vibudh
    Su, Mingwan
    Huang, Yuanshen
    Hsing, Michael
    Cherkasov, Artem
    Zhou, Youwen
    MOLECULES, 2019, 24 (19):
  • [47] QSAR modeling and in silico design of small-molecule inhibitors targeting the interaction between E3 ligase VHL and HIF-1α
    Pan, Jing
    Zhang, Yanmin
    Ran, Ting
    Xu, Anyang
    Qiao, Xin
    Yin, Lingfeng
    Zhou, Weineng
    Zhu, Lu
    Zhao, Junnan
    Lu, Tao
    Chen, Yadong
    Jiang, Yulei
    MOLECULAR DIVERSITY, 2017, 21 (03) : 719 - 739
  • [48] High-Throughput Selectivity Assays for Small-Molecule Inhibitors of β-Catenin/T-Cell Factor Protein-Protein Interactions
    Zhang, Min
    Catrow, J. Leon
    Ji, Haitao
    ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (02): : 306 - 311
  • [49] Computer-aided design and discovery of protein-protein interaction inhibitors as agents for anti-HIV therapy
    Veselovsky, A. V.
    Zharkova, M. S.
    Poroikov, V. V.
    Nicklaus, M. C.
    SAR AND QSAR IN ENVIRONMENTAL RESEARCH, 2014, 25 (06) : 457 - 471
  • [50] High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein-Protein Interaction
    Karatas, Hacer
    Townsend, Elizabeth C.
    Cao, Fang
    Chen, Yong
    Bernard, Denzil
    Liu, Liu
    Lei, Ming
    Dou, Yali
    Wang, Shaomeng
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135 (02) : 669 - 682