Computer Simulations Reveal a Novel Nucleotide-Type Binding Orientation for Ellipticine-Based Anticancer c-kit Kinase Inhibitorsâ 

Damien Thompson, Charlotte Miller, Florence O. McCarthy

Research output: Contribution to journalArticlepeer-review

Abstract

Receptor tyrosine kinase (RTK) enzymes regulate cell signaling pathways and so are an important target for cancer chemotherapy. Current inhibitors of c-kit, a key RTK stem cell factor receptor, are inactive against the most common mutated variant Asp816Val, associated with highly malignant cancers. Recent combined experimental/simulation work has highlighted the utility of the ellipticine pharmacore in inhibiting mutant c-kit, and the present simulation study applies a combination of high-level simulation tools to probe further the binding of ellipticine-based derivatives to c-kit. We find a large preference for protonation of bound ellipticine, which stabilizes the negative protein residues that coordinated ADP·Mg2+ in the native complex. The resulting ellipticine inhibitor binding mode resembles the native nucleotide complex and serves to explain some existing experimental data on binding specificities, indicating that functionalization at the C4/C5 sites of ellipticine derivatives may be important for the design of novel nucleotide analogues that inhibit mutant c-kit.

Original languageEnglish (Ireland)
Pages (from-to)10333-10344
Number of pages12
JournalBiochemistry
Volume47
Issue number39
DOIs
Publication statusPublished - 30 Sep 2008

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