STRUCTURE BASED APPROACH IN DRUG DISCOVERY AND IDENTIFICATION OF LIGAND BINDING SITES

S. Samar Hasnain and Svetlana Antonyuk

Barkla X-ray Laboratory of Biophysics, Institute of Integrative Biology, University of Liverpool, Liverpool, UK

Abstract

X-ray Structural Biology has transformed the way we think of biology and has allowed us to understand many biological processes at the molecular level. The tremendous success of structural biology during the last 30 years is largely owed to synchrotron X-ray facilities, advances in molecular biology techniques and compute power. In addition to fundamental biology, high resolution structure determination of soluble and membrane proteins has allowed knowledge-based lead compounds discovery/optimisation. We are engaged with the use of SR X-ray co-crystallography for a number of human target proteins that are involved in a number of diseases. These include CuZn superoxide dismutase (SOD1) [1-4] and cytochrome bc1 complex [5-6], which are validated targets for motor neuron disease and anti-malarial drugs, respectively.

REFERENCES

[1] G. S., Wright, S. V. Antonyuk, N. Kershaw, Strange, R. W. & Hasnain, S.S. (2013) Ligand binding and aggregation of pathogenic SOD1. Nature Communications 4, 1758. doi: 10.1038/ncomms2750.
[2] N. Kershaw, G. S. Wright, R. Sharma, S. V. Antonyuk, R. W. Strange, N. G. Berry,P. M. O’Neil and S.S. Hasnain (2013) X-ray crystallography and computational docking for the detection and development of protein-ligand interactions. Current Med Chem, 20, 569-75.
[3] S. Antonyuk, R. W. Strange and S. S. Hasnain (2010) Structural Discovery of Small Molecule Binding Sites in Cu-Zn Human Superoxide Dismutase Familial Amyotrophic Lateral Sclerosis Mutants Provides Insights for Lead Optimization. Journal of Medicinal Chemistry 53, 1402-1406.
[4] M. A. Hough, J. G. Grossmann, S. Antonyuk, R. W. Strange, P. A.Doucette, J. A. Rodriguez, L. J. Whitson, P. J. Hart, L. J. Hayward, J. S. Valentine and S. S. Hasnain (2004) Destabilisation of the Dimer Interface in SOD1 may result in disease causing properties: Structures of motor neuron disease mutants A4V and I113T. Proceedings of National Academy of Sciences: USA. 101, 5976-5981
[5] M. J. Capper, P. M. O'Neill, N. Fisher, R. W. Strange, D. Moss, S. A. Ward, N. G. Berry, A. S. Lawrenson, S. S. Hasnain, G. A. Biagini, S. V. Antonyuk (2015) Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1. Proceedings of National Academy of Sciences 112, 755-760 doi:10.1073/pnas.1416611112
[6] M. McPhillie, Y. Zhou, K. Bissati, J. Dubey, H. Lorenzi, M. Capper, A. K Lukens, M. Hickman, S. Muench, S. K. Verma, C. R. Weber, K. Wheeler, J. Gordon, J. Sanders, H. Moulton, K. Wang, T. K. Kim, Y. He, T. Santos, S. Woods, P. Lee, D. Donkin, E. Kim, L. Fraczek, J. Lykins, F. Esaa, F. Alibana-Clouser, S. Dovgin, L. Weiss, G. Brasseur, D. Wirth, M. Kent, L. Hood, B. Meunieur, C. W. Roberts, S. S. Hasnain, S. V. Antonyuk, C. Fishwick & Rima McLeod (2016) New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Scientific Reports | 6:29179 | DOI: 10.1038/srep29179.