Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction

Abstract

Free energy perturbation theory, in combination with enhanced sampling of protein-ligand binding modes, is evaluated in the context of fragment-based drug design, and used to design two new small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction.

Fig. 1. Crystal structure of AurkinA (compound 13) bound to Aurora A kinase. Flexible torsional angles in the ligand (φ) and L178 on the protein (χ) are shown in red.

Fig. 2. Examples of structures sampled during MC/FEP simulations of compound 2 bound to Aurora A. (a) φ = 180°, χ = 180°, (b) φ = 330°, χ = 180°, (c) φ = 180°, χ = 60°.

Fig. 3. Dihedral angle distributions from Monte Carlo simulations for both the phenyl ring of compounds 2 and 5 (φ) and the side chain of L178 (χ). Assigned dihedral angles from X-ray crystal structures are displayed as vertical dashed lines.

Fig. 4. Additional MC/FEP relative free energies of binding (kcal mol^–1) and experimental results where available.

Fig. 5. Correlation between computed and experimental (= RT ln(IC₅₀)) binding free energies. Computational results are offset to give the same mean as the experimental distribution.