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Targeting Metalloproteins by Fragment‐Based Lead Discovery
Author(s) -
Johnson Sherida,
Barile Elisa,
Farina Biancamaria,
Purves Angela,
Wei Jun,
Chen LiHsing,
Shiryaev Sergey,
Zhang Ziming,
Rodionova Irina,
Agrawal Arpita,
Cohen Seth M.,
Osterman Andrei,
Strongin Alex,
Pellecchia Maurizio
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01136.x
Subject(s) - pharmacophore , drug discovery , metalloprotein , computational biology , chemistry , combinatorial chemistry , virtual screening , fragment (logic) , structural bioinformatics , high throughput screening , biochemistry , nanotechnology , enzyme , biology , protein structure , computer science , materials science , programming language
It has been estimated that nearly one‐third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high‐throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal‐binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment‐based drug discovery approach using a metal‐targeting fragment library that is based on a variety of distinct classes of metal‐binding groups designed to reliably anchor the fragments at the target’s metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein‐targeted therapeutics.