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Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR.

Abstract：

:4-Anilino-3-cyanoquinolines were reported to have irreversible binding to epidermal growth factor receptor kinase (EGFRK) by forming a covalent linkage to C773. Our initial docking studies gave results inconsistent with the in vitro data and showed two different binding modes. To perceive the exact mode of binding of these ligands, two models of the ligand-EGFR complexes were considered: (1) reversible binding mode in which the ligand had hydrogen bond interactions at the binding site and (2) irreversible binding mode wherein the ligand's Michael acceptor side chain has proximity to the sulfhydryl group of C773 of EGFR, thereby enabling a covalent interaction. The irreversible binding mode correlated better than reversible binding mode with respect to in vitro data. However, our results indicate that both modes are being adopted by the ligands and could be utilized to design more potent EGFRK inhibitors.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Akula N,Bhalla J,Sridhar J,Pattabiraman N

doi

10.1016/j.bmcl.2004.04.080

subject

Has Abstract

pub_date

2004-07-05 00:00:00

pages

3397-400

issue

13

eissn

0960-894X

issn

1464-3405

pii

S0960894X04005955

journal_volume

14

pub_type

杂志文章

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