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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.)

Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor

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Author(s):
de Freitas, Renato Ferreira [1] ; Ivanochko, Danton [2, 3, 4] ; Schapira, Matthieu [5, 4]
Total Authors: 3
Affiliation:
[1] Univ Fed ABC, Ctr Ciencias Nat & Humanas, Rua Arcturus 3, BR-09606070 Sao Bernardo Do Campo, SP - Brazil
[2] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9 - Canada
[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9 - Canada
[4] Univ Toronto, MaRS Ctr, Struct Genom Consortium, South Tower, 101 Coll St, Suite 700, Toronto, ON M5G 1L7 - Canada
[5] Univ Toronto, Dept Pharmacol & Toxicol, 1 Kings Coll Circle, Toronto, ON M5S 1A8 - Canada
Total Affiliations: 5
Document type: Review article
Source: Molecules; v. 24, n. 24 DEC 2019.
Web of Science Citations: 0
Abstract

Protein methyltransferases (PMTs) are enzymes involved in epigenetic mechanisms, DNA repair, and other cellular machineries critical to cellular identity and function, and are an important target class in chemical biology and drug discovery. Central to the enzymatic reaction is the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Here we review how the essentiality of SAM for catalysis is exploited by chemical inhibitors. Occupying the cofactor binding pocket to compete with SAM can be hindered by the hydrophilic nature of this site, but structural studies of compounds now in the clinic revealed that inhibitors could either occupy juxtaposed pockets to overlap minimally, but sufficiently with the bound cofactor, or induce large conformational remodeling leading to a more druggable binding site. Rather than competing with the cofactor, other inhibitors compete with the substrate and rely on bound SAM, either to allosterically stabilize the substrate binding site, or for direct SAM-inhibitor interactions. (AU)

FAPESP's process: 18/11011-7 - Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches
Grantee:Renato Ferreira de Freitas
Support Opportunities: Research Grants - Young Investigators Grants
FAPESP's process: 19/08603-2 - Design of inhibitors of kallikreins 5, 6, and 7 using computational methods and fragment-based approaches
Grantee:Renato Ferreira de Freitas
Support Opportunities: Scholarships in Brazil - Young Researchers