Binding selectivity analysis of AURKs inhibitors through molecular dynamics simulation studies

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Pharmacology

Background:

• Aurora kinases (AURKs) are crucial regulators of cell division and are implicated as significant therapeutic targets in oncology.
• Developing selective inhibitors for AURKA and AURKB is essential for effective cancer treatment, minimizing off-target effects.

Purpose of the Study:

• To investigate the binding selectivity of three small molecule inhibitors (HPM, MPY, VX6) against Aurora Kinase A (AURKA) and Aurora Kinase B (AURKB).
• To elucidate the molecular interactions and dynamic factors governing the differential binding affinities of these inhibitors.

Main Methods:

• Molecular dynamics (MD) simulations were utilized to predict binding free energies between the inhibitors and both AURKA and AURKB.
• Binding energy decomposition analysis was performed to identify specific residue interactions contributing to selectivity.
• MD trajectory analysis was employed to assess the impact of inhibitors on protein structural dynamics.

Main Results:

• All three inhibitors (HPM, MPY, VX6) demonstrated more favorable binding interactions with AURKB compared to AURKA.
• Specific residue pairs, including (L139, L83), (V147, V91), (L210, L154), and (L263, L207), were identified as critical for selective binding.
• Inhibitor binding influenced the dynamic flexibility of the protein structures, contributing to partial selectivity.

Conclusions:

• The study successfully characterized the binding selectivity of HPM, MPY, and VX6 towards AURKB over AURKA.
• Key molecular determinants and dynamic effects responsible for this selectivity were elucidated.
• Findings provide valuable insights for the rational design of novel, highly selective AURKA/AURKB inhibitors for cancer therapy.