Strategy to target the substrate binding site of SET domain protein methyltransferases.
J Chem Inf Model
; 53(3): 681-91, 2013 Mar 25.
Article
in En
| MEDLINE
| ID: mdl-23410263
ABSTRACT
Protein methyltransferases (PMTs) are a novel gene family of therapeutic relevance involved in chromatin-mediated signaling and other biological mechanisms. Most PMTs are organized around the structurally conserved SET domain that catalyzes the methylation of a substrate lysine. A few potent chemical inhibitors compete with the protein substrate, and all are anchored in the channel recruiting the methyl-accepting lysine. We propose a novel strategy to design focused chemical libraries targeting the substrate binding site, where a limited number of warheads each occupying the lysine-channel of multiple enzymes would be decorated by different substituents. A variety of sequence and structure-based approaches used to analyze the diversity of the lysine channel of SET domain PMTs support the relevance of this strategy. We show that chemical fragments derived from published inhibitors are valid warheads that can be used in the design of novel focused libraries targeting other PMTs.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Methyltransferases
Language:
En
Journal:
J Chem Inf Model
Journal subject:
INFORMATICA MEDICA
/
QUIMICA
Year:
2013
Type:
Article
Affiliation country:
Canada