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

Daniel J Cole; Matej Janecek; Jamie E Stokes; Maxim Rossmann; John C Faver; Grahame J McKenzie; Ashok R Venkitaraman; Marko Hyvönen; David R Spring; David J Huggins; William L Jorgensen

doi:10.1039/c7cc05379g

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

Chem Commun (Camb). 2017 Aug 17;53(67):9372-9375. doi: 10.1039/c7cc05379g.

Authors

Affiliations

¹ Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA and School of Chemistry, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. daniel.cole@ncl.ac.uk.
² MRC Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK and Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
³ Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
⁴ Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge CB2 1GA, UK.
⁵ Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
⁶ MRC Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
⁷ MRC Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK and Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK and Theory of Condensed Matter Group, Cavendish Laboratory, 19 JJ Thomson Avenue, Cambridge CB3 0HE, UK.

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.

MeSH terms

Aurora Kinase A / antagonists & inhibitors*
Aurora Kinase A / chemistry
Aurora Kinase A / metabolism
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / metabolism
Humans
Microtubule-Associated Proteins / antagonists & inhibitors*
Microtubule-Associated Proteins / chemistry
Microtubule-Associated Proteins / metabolism
Models, Molecular
Molecular Dynamics Simulation*
Molecular Structure
Nuclear Proteins / antagonists & inhibitors*
Nuclear Proteins / chemistry
Nuclear Proteins / metabolism
Protein Binding / drug effects
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

Cell Cycle Proteins
Microtubule-Associated Proteins
Nuclear Proteins
Protein Kinase Inhibitors
Small Molecule Libraries
TPX2 protein, human
Aurora Kinase A

Abstract

MeSH terms

Substances

Grants and funding