Hostname: page-component-78c5997874-t5tsf Total loading time: 0 Render date: 2024-11-13T03:45:48.922Z Has data issue: false hasContentIssue false
  • English
  • Français

An in silico structure-based approach to anti-infective drug discovery

Published online by Cambridge University Press:  17 June 2013

FRASER CUNNINGHAM ,
MARTIN J. McPHILLIE ,
A. PETER JOHNSON  and
COLIN W. G. FISHWICK
FRASER CUNNINGHAM
Affiliation:
School of Chemistry, University of Leeds, Leeds, UK
MARTIN J. McPHILLIE
Affiliation:
School of Chemistry, University of Leeds, Leeds, UK
A. PETER JOHNSON
Affiliation:
School of Chemistry, University of Leeds, Leeds, UK
COLIN W. G. FISHWICK*
Affiliation:
School of Chemistry, University of Leeds, Leeds, UK
*
*Corresponding author. School of Chemistry, University of Leeds, Leeds, UK. Tel: +44 (0)113 3436510. Fax: +44 (0) 113 343 6565 E-mail: C.W.G.Fishwick@leeds.ac.uk
Get access Rights & Permissions [Opens in a new window]

Summary

In light of the low success rate of target-based genomics and HTS (High Throughput Screening) approaches in anti-infective drug discovery, in silico structure-based drug design (SBDD) is becoming increasingly prominent at the forefront of drug discovery. In silico SBDD can be used to identify novel enzyme inhibitors rapidly, where the strength of this approach lies with its ability to model and predict the outcome of protein-ligand binding. Over the past 10 years, our group have applied this approach to a diverse number of anti-infective drug targets ranging from bacterial D-ala-D-ala ligase to Plasmodium falciparum DHODH. Our search for new inhibitors has produced lead compounds with both enzyme and whole-cell activity with established on-target mode of action. This has been achieved with greater speed and efficiency compared with the more traditional HTS initiatives and at significantly reduced cost and manpower.

Keywords

in silico drug discoverymalariaDHODHbacterial resistanceRNA polymeraseD-ala-D-ala ligase
Type
Research Article
Information
Parasitology , Volume 141 , Issue 1: Symposia of the British Society for Parasitology volume 49 Emerging paradigms in anti-infective drug design , January 2014 , pp. 17 - 27
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Agarwal, A. K., Johnson, A. P. and Fishwick, C. W. G. (2008). Synthesis of de novo designed small-molecule inhibitors of bacterial RNA polymerase. Tetrahedron 64, 10049–10054. doi: http://dx.doi.org/10.1016/j.tet.2008.08.037.Google Scholar
Bedingfield, P. T., Cowen, D., Acklam, P., Cunningham, F., Parsons, M. R., McConkey, G. A., Fishwick, C. W. and Johnson, A. P. (2012). Factors influencing the specificity of inhibitor binding to the human and malaria parasite dihydroorotate dehydrogenases. Journal of Medicinal Chemistry 55, 5841–5850. doi: 10.1021/jm300157n.Google Scholar
Besong, G. E., Bostock, J. M., Stubbings, W., Chopra, I., Roper, D. I., Lloyd, A. J., Fishwick, C. W. G. and Johnson, A. P. (2005). A de novo designed inhibitor of D-ala–D-ala ligase from E. coli. Angewandte Chemie International Edition 44, 6403–6406. doi: 10.1002/anie.200501662.Google Scholar
Bruneau, J.-M., Yea, C. M., Spinella-Jaegle, S., Fudali, C., Woodward, K., Robson, P. A., Sautes, C., Westwood, R., Kuo, E. A., Williamson, R. A. and Ruuth, E. (1998). Purification of human dihydroorotate dehydrogenase and its Inhibition by A77–1726, the active metabolite of leflunomide. Biochemical Journal 336, 5.CrossRefGoogle ScholarPubMed
Calderón, F., Barros, D., Bueno, J. M., Coterón, J. M., Fernández, E., Gamo, F. J., Lavandera, J. L., León, M. L., Macdonald, S. J. F., Mallo, A., Manzano, P., Porras, E., Fiandor, J. M. and Castro, J. (2011). An invitation to open innovation in malaria drug discovery. ACS Medicinal Chemistry Letters 2, 741–746. doi: 10.1021/ml200135p.Google Scholar
Campbell, E. A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A. and Darst, S. A. (2001). Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 104, 901–912.Google Scholar
Chopra, I. (2007). Bacterial RNA Polymerase: a promising target for the discovery of new antimicrobial agents. Current Opinion in Investgational Drugs 8, 600–607.Google Scholar
Christopherson, R. I., Lyons, S. D. and Wilson, P. K. (2002). Inhibitors of de novo nucleotide biosynthesis as drugs. Accounts of Chemical Research 35, 961–971. doi: 10.1021/ar0000509.Google Scholar
Coates, A. R. M., Halls, G. and Hu, Y. (2011). Novel classes of antibiotics or more of the same? British Journal of Pharmacology 163, 184–194. doi: 10.1111/j.1476–5381.2011.01250.x.Google Scholar
Cramer, P., Bushnell, D. A. and Kornberg, R. D. (2001). Structural basis of transcription: RNA polymerase II at 2·8 Ångstrom resolution. Science 292, 1863–1876. doi: 10.1126/science.1059493.Google Scholar
Daubendiek, S. L., Ryan, K. and Kool, E. T. (1995). Rolling-circle RNA synthesis: circular oligonucleotides as efficient substrates for T7 RNA polymerase. Journal of the American Chemical Society 117, 7818–7819. doi: 10.1021/ja00134a032.Google Scholar
Davies, M., Heikkila, T., McConkey, A. G., Fishwick, C. W., Parsons, M. R. and Johnson, A. P. (2009). Structure-based design, synthesis and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases. Journal of Medicinal Chemistry 52, 11.Google Scholar
Fan, C., Moews, P., Walsh, C. and Knox, J. R. (1994). Vancomycin resistance: structure of D-alanine:D-alanine ligase at 2·3 A resolution. Science 266, 439–443. doi: 10.1126/science.7939684.Google Scholar
Fang, J., Uchiumi, T., Yagi, M., Matsumoto, S., Amaoto, R., Takazaki, S., Yamaza, H., Nonaka, K. and Kang, D. (2012). Dihydroorotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. Bioscience Reports 33, 217–227. doi: 10.1042/BSR20120097.Google Scholar
Gillet, V. J., Newell, W., Mata, P., Myatt, G., Sike, S., Zsoldos, Z. and Johnson, A. P. (1994). SPROUT - Recent developments in the de novo design of molecules. Journal of Chemical Information and Computer Sciences 34, 207–217. doi: 10.1021/ci00017a027.Google Scholar
Grant, J. A., Gallardo, M. A. and Pickup, B. T. (1996). A fast method of molecular shape comparison: a simple application of a Gaussian description of molecular shape. Journal of Computational Chemistry 17, 1653–1666. doi: 10.1002/(sici)1096–987x(19961115)17:14<1653::aid-jcc7>3.0.co;2-k.Google Scholar
Green, D. W. (2002). The bacterial cell wall as a source of antibacterial targets. Expert Opinion on Therapeutic Targets 6, 1–20. doi:10.1517/14728222.6.1.1.Google Scholar
Haque, T. S., Tadesse, S., Marcinkeviciene, J., Rogers, M. J., Sizemore, C., Kopcho, L. M., Amsler, K., Ecret, L. D., Zhan, D. L., Hobbs, F., Slee, A., Trainor, G. L., Stern, A. M., Copeland, R. A. and Combs, A. P. (2002). Parallel synthesis of potent, pyrazole-based inhibitors of Helicobacter pylori dihydroorotate dehydrogenase. Journal of Medicinal Chemistry 45, 4669–4678. doi: 10.1021/jm020112w.Google Scholar
Heikkila, T. (2007). Dihydroorotate dehydrogenases: biochemical characterisation and structure-based inhibitor development. In Biology, Vol. Doctor of Philosophy University of Leeds, Leeds.Google Scholar
Heikkila, T., Ramsey, C., Davies, M., Galtier, C., Stead, A. M., Johnson, A. P., Fishwick, C. W., Boa, A. N. and McConkey, G. A. (2007). Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. Journal of Medicinal Chemistry 50, 186–191. doi: 10.1021/jm060687j.Google Scholar
Heikkila, T., Thirumalairajan, S., Davies, M., Parsons, M. R., McConkey, A. G., Fishwick, C. W. and Johnson, A. P. (2006). The first de novo designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. Bioorganic and Medicinal Chemistry Letters 16, 88–92. doi: 10.1016/j.bmcl.2005.09.045.Google Scholar
Hines, V., Keys, L. D. and Johnston, M. (1986). Purification and properties of the bovine liver mitochondrial dihydroorotate dehydrogenase. Journal of Biological Chemistry 261, 1386–1392.Google Scholar
Huey, R., Morris, G. M., Olson, A. J. and Goodsell, D. S. (2007). A semiempirical free energy force field with charge-based desolvation. Journal of Computational Chemistry 28, 1145–1152. doi: 10.1002/jcc.20634.Google Scholar
Hurt, D. E., Widom, J. and Clardy, J. (2006). Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. Acta crystallographica. Section D, Biological Crystallography. 62(Pt 3), 312–323. doi: 10.1107/S0907444905042642.Google Scholar
Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T. and Clardy, J. (2000). Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure 8, 9.Google Scholar
Livermore, D. M. (2011). Discovery research: the scientific challenge of finding new antibiotics. Journal of Antimicrobial Chemotherapy 66, 1941–1944. doi: 10.1093/jac/dkr262.Google Scholar
López-Vallejo, F., Giulianotti, M. A., Houghten, R. A. and Medina-Franco, J. L. (2012). Expanding the medicinally relevant chemical space with compound libraries. Drug Discovery Today 17, 718–726. doi: http://dx.doi.org/10.1016/j.drudis.2012.04.001.Google Scholar
McPhillie, M. J., Trowbridge, R., Mariner, K. R., O'Neill, A. J., Johnson, A. P., Chopra, I. and Fishwick, C. W. G. (2011). Structure-based ligand design of novel bacterial RNA polymerase inhibitors. ACS Medicinal Chemistry Letters 2, 729–734. doi: 10.1021/ml200087m.Google Scholar
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S. and Olson, A. J. (2009). AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry 30, 2785–2791. doi: 10.1002/jcc.21256.Google Scholar
Mukhopadhyay, J., Das, K., Ismail, S., Koppstein, D., Jang, M., Hudson, B., Sarafianos, S., Tuske, S., Patel, J., Jansen, R., Irschik, H., Arnold, E. and Ebright, R. H. (2008). The RNA polymerase switch region is a target for inhibitors. Cell 135, 295–307.Google Scholar
Olliaro, P. and Wells, T. N. (2009). The global portfolio of new antimalarial medicines under development. Clinical Pharmacology and Therapeutics 85, 584–595. doi: 10.1038/clpt.2009.51.Google Scholar
Phillips, M. A., Gujjar, R., Malmquist, N. A., White, J., El Mazouni, F., Baldwin, J. and Rathod, P. K. (2008). Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum. Journal of Medicinal Chemistry 51, 3649–3653. doi: 10.1021/jm8001026.Google Scholar
Seidler, J., McGovern, S. L., Doman, T. N. and Shoichet, B. K. (2003). Identification and prediction of promiscuous aggregating inhibitors among known drugs. Journal of Medicinal Chemistry 46, 4477–4486. doi: 10.1021/jm030191r.Google Scholar
Simmons, K. J., Chopra, I. and Fishwick, C. W. (2010). Structure-based discovery of antibacterial drugs. Nature Reviews Microbiology 8, 501–510. doi: 10.1038/nrmicro2349.Google Scholar
Srivastava, A., Talaue, M., Liu, S., Degen, D., Ebright, R. Y., Sineva, E., Chakraborty, A., Druzhinin, S. Y., Chatterjee, S., Mukhopadhyay, J., Ebright, Y. W., Zozula, A., Shen, J., Sengupta, S., Niedfeldt, R. R., Xin, C., Kaneko, T., Irschik, H., Jansen, R., Donadio, S., Connell, N. and Ebright, R. H. (2011). New target for inhibition of bacterial RNA polymerase: ‘switch region’. Current Opinion in Microbiology 14, 532–543. doi: http://dx.doi.org/10.1016/j.mib.2011.07.030.Google Scholar
Stahl, M., Guba, W. and Kansy, M. (2006). Integrating molecular design resources within modern drug discovery research: the Roche experience. Drug Discovery Today 11, 326–333. doi: 10.1016/j.drudis.2006.02.008.Google Scholar
Wenzel, R. P. and Edmond, M. B. (2000). Managing antibiotic resistance. New England Journal of Medicine 343, 1961–1963. doi: 10.1056/NEJM200012283432610.Google Scholar
White, N. (1999). Antimalarial drug resistance and combination chemotherapy. Philosophical Transactions of the Royal Society of London Series B-Biological Sciences 354, 739–749. doi: 10.1098/rstb.1999.0426.Google Scholar
WHO (2011). World Malaria Report 2011. World Health Organisation, Geneva, Switzerland.Google Scholar
Zsoldos, Z., Reid, D., Simon, A., Sadjad, S. B. and Johnson, A. P. (2007). eHiTS: a new fast, exhaustive flexible ligand docking system. Journal of Molecular Graphics and Modelling 26, 198–212. doi: 10.1016/j.jmgm.2006.06.002.Google Scholar