doi:10.1038/nindia.2014.103 Published online 29 July 2014
Quick, economic tool for drug discovery
Researchers have devised a drug-discovery tool that can be used to study the interactions between potential drug molecules and target proteins1. They demonstrated the usefulness of this tool, which is based on surface-enhance Raman spectroscopy, by using it to uncover how felodipine (a widely used blood-pressure-lowering drug) binds to and inhibits the activity of Aurora A kinase (an enzyme that aids tumour growth). This drug-discovery tool is potentially useful for identifying new drug molecules for treating various diseases, including cancers.
The researchers used a combination of surface-enhanced Raman spectroscopy and molecular dynamics simulations to probe the efficiency of felodipine to selectively bind to and inhibit Aurora A kinase. They studied the spectra of Aurora A kinase in free and complex forms with felodipine and compared them with those of Aurora B kinase, a similar class of enzyme.
The researchers found that the spectrum of Aurora A kinase underwent a significant change when the enzyme bound to felodipine and that its spectrum differed from that of Aurora B kinase. By applying molecular docking analysis, they detected the cause of this change to the spectrum, namely felodipine cannot bind to Aurora B kinase as it has a smaller felodipine-binding site than Aurora A kinase.
The researchers then validated these results by carrying out experiments using cultured cervical, breast and colon cancer cells and mice with brain tumours. They found that felodipine selectively inhibited the activity of Aurora A kinase, resulting in the death of cancer cells. In mice, felodipine treatment significantly reduced tumour growth by inhibiting the activity of Aurora A kinase. These results indicate that felodipine could be used as a potent anticancer drug.
“Since this drug-discovery technique is fast and cost-effective, it can potentially be used to handle multiple samples to develop a platform for screening drug molecules,” says Tapas K. Kundu, a senior author of the study.
The authors of this work are from: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Light Scattering Laboratory, Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore and Department of Studies in Chemistry, University of Mysore, Mysore, India and Department of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
1. Karthigeyan, D. et al. SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool. Proc. Natl Acad. Sci. USA. 111, 10416–10421 (2014) doi: 10.1073/pnas.1402695111