An Integrated in silico Approach and in vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies.
Antineoplastic Agents
/ chemistry
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors
/ chemistry
Humans
Molecular Dynamics Simulation
Molecular Structure
Neoplasms
/ drug therapy
Small Molecule Libraries
/ chemistry
Structure-Activity Relationship
Ubiquitin-Specific Peptidase 7
/ antagonists & inhibitors
cancer
drug design
inhibitors
pharmacophores
ubiquitin specific protease 7 (USP7)
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
04 02 2021
04 02 2021
Historique:
received:
28
08
2020
revised:
06
10
2020
pubmed:
17
10
2020
medline:
11
11
2021
entrez:
16
10
2020
Statut:
ppublish
Résumé
The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
Identifiants
pubmed: 33063944
doi: 10.1002/cmdc.202000675
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Small Molecule Libraries
0
USP7 protein, human
EC 3.4.19.12
Ubiquitin-Specific Peptidase 7
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
555-567Subventions
Organisme : Bahçeşehir University, Scientific Research Projects Unit
Informations de copyright
© 2020 Wiley-VCH GmbH.
Références
J. A. Harrigan, X. Jacq, N. M. Martin, S. P. Jackson, Nat. Rev. Drug Discovery 2017, 17, 57.
B. Nicholson, J. G. Marblestone, T. R. Butt, M. R. Mattern, Future Oncol. 2007, 3, 191-199.
P. Gopinath, S. Ohayon, M. Nawatha, A. Brik, Chem. Soc. Rev. 2016, 45, 4171-4198;
J. J. Sacco, J. M. Coulson, M. J. Clague, S. Urbe, IUBMB Life 2010, 62, 140-157.
C. Ndubaku, V. Tsui, J. Med. Chem. 2015, 58, 1581-1595.
A. H. Tencer, Q. Liang, Z. Zhuang, Biochemistry 2016, 55, 4708-4719.
R. Pfoh, I. K. Lacdao, V. Saridakis, Endocr.-Relat. Cancer 2015, 22, T35-T54.
B. Cvek, Z. Dvorak, Drug Discovery Today 2008, 13, 716-722.
T. Yuan, F. Yan, M. Ying, J. Cao, Q. He, H. Zhu, B. Yang, Front. Pharmacol. 2018, 9, 1080-1080.
J. Weinstock, J. Wu, P. Cao, W. D. Kingsbury, J. L. McDermott, M. P. Kodrasov, D. M. McKelvey, K. G. Suresh Kumar, S. J. Goldenberg, M. R. Mattern, B. Nicholson, ACS Med. Chem. Lett. 2012, 3, 789-792.
G. Gavory, C. R. O′Dowd, M. D. Helm, J. Flasz, E. Arkoudis, A. Dossang, C. Hughes, E. Cassidy, K. McClelland, E. Odrzywol, N. Page, O. Barker, H. Miel, T. Harrison, Nat. Chem. Biol. 2018, 14, 118-125.
I. Lamberto, X. Liu, H. S. Seo, N. J. Schauer, R. E. Iacob, W. Hu, D. Das, T. Mikhailova, E. L. Weisberg, J. R. Engen, K. C. Anderson, D. Chauhan, S. Dhe-Paganon, S. J. Buhrlage, Cell Chem. Biol. 2017, 24, 1490-1500.e1411;
L. Deng, T. Meng, L. Chen, W. Wei, P. Wang, Signal Transduct Target Ther 2020, 5, 11.
C. R. O′Dowd, M. D. Helm, J. S. S. Rountree, J. T. Flasz, E. Arkoudis, H. Miel, P. R. Hewitt, L. Jordan, O. Barker, C. Hughes, E. Rozycka, E. Cassidy, K. McClelland, E. Odrzywol, N. Page, S. Feutren-Burton, S. Dvorkin, G. Gavory, T. Harrison, ACS Med. Chem. Lett. 2018, 9, 238-243;
A. P. Turnbull, S. Ioannidis, W. W. Krajewski, A. Pinto-Fernandez, C. Heride, A. C. L. Martin, L. M. Tonkin, E. C. Townsend, S. M. Buker, D. R. Lancia, J. A. Caravella, A. V. Toms, T. M. Charlton, J. Lahdenranta, E. Wilker, B. C. Follows, N. J. Evans, L. Stead, C. Alli, V. V. Zarayskiy, A. C. Talbot, A. J. Buckmelter, M. Wang, C. L. McKinnon, F. Saab, J. F. McGouran, H. Century, M. Gersch, M. S. Pittman, C. G. Marshall, T. M. Raynham, M. Simcox, L. M. D. Stewart, S. B. McLoughlin, J. A. Escobedo, K. W. Bair, C. J. Dinsmore, T. R. Hammonds, S. Kim, S. Urbe, M. J. Clague, B. M. Kessler, D. Komander, Nature 2017, 550, 481-486.
Schrodinger, Maestro, LLC, New York, NY, 2016.
G. M. Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman, J. Comput.-Aided Mol. Des. 2013, 27, 221-234.
D. C. Bas, D. M. Rogers, J. H. Jensen, Proteins Struct. Funct. Bioinf. 2008, 73, 765-783;
H. Li, A. D. Robertson, J. H. Jensen, Proteins Struct. Funct. Bioinf. 2005, 61, 704-721.
E. Harder, W. Damm, J. Maple, C. Wu, M. Reboul, J. Y. Xiang, L. Wang, D. Lupyan, M. K. Dahlgren, J. L. Knight, J. W. Kaus, D. S. Cerutti, G. Krilov, W. L. Jorgensen, R. Abel, R. A. Friesner, J. Chem. Theory Comput. 2016, 12, 281-296.
Schrodinger, LigPrep, LLC, New York, NY, 2016.
J. C. Shelley, A. Cholleti, L. L. Frye, J. R. Greenwood, M. R. Timlin, M. Uchimaya, J. Comput.-Aided Mol. Des. 2007, 21, 681-691;
Schrodinger, Epik, LLC, New York, NY, 2016.
Schrodinger, MacroModel, LLC, New York, NY, 2016.
R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, M. P. Repasky, E. H. Knoll, M. Shelley, J. K. Perry, D. E. Shaw, P. Francis, P. S. Shenkin, J. Med. Chem. 2004, 47, 1739-1749;
R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, P. C. Sanschagrin, D. T. Mainz, J. Med. Chem. 2006, 49, 6177-6196;
T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, J. L. Banks, J. Med. Chem. 2004, 47, 1750-1759;
Schrodinger, Glide, LLC, New York, NY, 2016.
T. Kanan, D. Kanan, I. Erol, S. Yazdi, M. Stein, S. Durdagi, J. Mol. Graphics Modell. 2019, 86, 264-277.
K. Loving, N. K. Salam, W. Sherman, J. Comput.-Aided Mol. Des. 2009, 23, 541-554.
N. K. Salam, R. Nuti, W. Sherman, J. Chem. Inf. Model. 2009, 49, 2356-2368;
S. L. Dixon, A. M. Smondyrev, S. N. Rao, Chem. Biol. Drug Des. 2006, 67, 370-372.
Schrodinger, Phase, LLC, New York, NY 2015;
S. L. Dixon, A. M. Smondyrev, E. H. Knoll, S. N. Rao, D. E. Shaw, R. A. Friesner, J. Comput.-Aided Mol. Des. 2006, 20, 647-671.
D. A. Evans, T. N. Doman, D. A. Thorner, M. J. Bodkin, J. Chem. Inf. Model. 2007, 47, 1248-1257;
S. S. Narkhede, M. S. Degani, QSAR Comb. Sci. 2007, 26, 744-753;
N. R. Tawari, S. Bag, M. S. Degani, J. Mol. Model. 2008, 14, 911-921.
S.-Y. Yang, Drug Discovery Today 2010, 15, 444-450.
D. E. S. Research, Desmond Molecular Dynamics System, LLC, New York, NY, 2016;
Schrodinger, Prime, LLC, New York, NY, 2016;
Schrodinger, Maestro-Desmond Interoperability Tools, LLC, New York, NY, 2016.
W. G. Hoover, Phys. Rev. A 1985, 31, 1695-1697.
G. J. Martyna, D. J. Tobias, M. L. Klein, J. Chem. Phys. 1994, 101, 4177-4189.
B. R. Miller, T. D. McGee, J. M. Swails, N. Homeyer, H. Gohlke, A. E. Roitberg, J. Chem. Theory Comput. 2012, 8, 3314-3321.
L. Jianing, A. Robert, Z. Kai, C. Yixiang, Z. Suwen, F. R. A., Proteins Struct. Funct. Bioinf. 2011, 79, 2794-2812.