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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5 `-Nucleotidase Inhibitors

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Author(s):
Viviani, Lucas G. [1] ; Piccirillo, Erika [1, 2] ; Ulrich, Henning [2] ; Amaral, Antonia T-do [1]
Total Authors: 4
Affiliation:
[1] Univ Sao Paulo, Inst Chem, Dept Fundamental Chem, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Chem, Dept Biochem, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo - Brazil
Total Affiliations: 2
Document type: Journal article
Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 621-630, FEB 2020.
Web of Science Citations: 1
Abstract

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) is a zinc-binding metallophosphatase that plays a key role in extracellular purinergic pathways, being implicated in several physiological and pathophysiological processes, such as immune homeostasis, inflammation, and tumor progression. As such, it has been recognized as a promising biological target for many diseases, including cancer, infections, and autoimmune diseases. Despite its importance, so far only a few inhibitors of this target enzyme are known, most of which are not suitable as drug candidates. Here, we aimed to search for hydroxamic acid-containing compounds as potential human ecto-5'-NT inhibitors, since this group is known to be a strong zinc chelator. To this end, we performed a hierarchical virtual screening (VS) search consisting of three consecutive steps (filtering for compounds bearing a hydroxamic acid group, shape-based matching, and docking followed by visual inspection), which were applied to screen the ZINC-14 database ({''}all purchasable subset{''}). Out of 25 compounds selected by this VS protocol, 12 were acquired and further submitted to enzymatic assays for VS experimental validation. Four of them (i.e., 33.3%) were found to inhibit human ecto-5'-NT in the low micromolar range. The most potent one showed an IC50 value of 6.2 +/- 1.0 mu M. All identified inhibitors satisfy drug-like criteria and provide novel scaffolds to be explored in further hit-to-lead optimization steps. Furthermore, to the best of our knowledge, they are the first hydroxamic acid-containing inhibitors of human ecto-5'-NT described so far. (AU)

FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
Grantee:Alexander Henning Ulrich
Support type: Research Projects - Thematic Grants
FAPESP's process: 18/24678-0 - Virtual screening of novel pathological angiogenesis inhibitors
Grantee:Erika Piccirillo
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 14/07248-0 - Virtual screening search for inhibitors of human ecto-5'-nucleotidase and of Mycobacterium tuberculosis thiorredoxin reductase: models generation and experimental validation
Grantee:Lucas Gasparello Viviani
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 18/06381-0 - Use of molecular dynamics (MD) simulations to study human ecto-5'-nucleotidase (ecto-5'NT, CD73) flexibility and TRAPP (Transient Pockets in Proteins) for protein binding site dynamics analyses
Grantee:Lucas Gasparello Viviani
Support type: Scholarships abroad - Research Internship - Doctorate (Direct)
FAPESP's process: 12/50880-4 - Stem cells: from basic studies of kinin and purinergic receptor roles towards therapeutical applications
Grantee:Alexander Henning Ulrich
Support type: Research Projects - Thematic Grants
FAPESP's process: 12/06633-2 - Rational search for inhibitors of Dengue and Foot-and-Mouth Disease proteases
Grantee:Erika Piccirillo
Support type: Scholarships in Brazil - Doctorate (Direct)