Discovery of novel Mnk inhibitors using mutation-based induced-fit virtual high-throughput screening

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Mitogen-activated protein kinase (Map) kinase pathways activate Mnk kinases (Mnk1 and 2).
• Mnk kinases regulate eukaryotic initiation factor 4E phosphorylation.
• Mnk pathway activation is crucial in acute myeloid leukemia (AML) development.

Purpose of the Study:

• To identify novel inhibitors of Mnk kinases.
• To explore a new structure-based drug design strategy for Mnk inhibitors.
• To evaluate the therapeutic potential of Mnk inhibitors in AML.

Main Methods:

• Development of a mutation-based induced-fit in silico screening approach.
• Modeling of the Mnk1 structure by mutating an amino acid in the ATP-binding site.
• Docking simulations of known inhibitors and screening for novel compounds.

Main Results:

• Identified novel Mnk inhibitor compounds through in silico screening.
• Validated hit compounds in biochemical and cellular assays.
• Demonstrated activity against acute myeloid leukemia progenitors.

Conclusions:

• The mutation-based induced-fit in silico screen is effective for identifying Mnk inhibitors.
• Targeting Mnk kinases represents a promising therapeutic strategy for AML.
• This approach facilitates rational drug design for novel kinase inhibitors.