Abstract
De novo design provides an in silico toolkit for the design of novel molecular structures to a set of specified structural constraints, and is thus ideally suited for creating molecules for chemical genomics. The design process involves manipulation of the input, modification of structural constraints, and further processing of the de novo-generated molecules using various modular toolkits. The development of a theoretical framework for each of these stages will provide novel practical solutions to the problem of creating compounds with maximal chemical diversity. This chapter describes the fundamental problems encountered in the application of novel chemical design technologies to chemical genomics by means of a formal representation. Formal representations help to outline and clarify ideas and hypotheses that can then be explored using mathematical algorithms. It is only by developing this rigorous foundation, that in silico design can progress in a rational way.
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References
Read, J., Pearce, J., Li, X., Muirhead, H., Chirgwin, J., and Davies, C. (2001) The crystal structure of human phosphoglucose isomerase at 1.6Å resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia. J. Mol. Biol. 309, 447–463.
Tsutsumi, S., Yanagawa, T., Shimura, T., et al. (2003) Regulation of cell proliferation by autocrine motility factor/phospoglucose isomerase signaling. J. Biol. Chem. 278, 32, 32,165–32,172.
Ohi, M. D., Vander Kooi, C. W., Rosenberg, J. A., Chazin, W. J., and Gould, K. L. (2003) Structural insights into the U-box, a domain associated with multi-ubiquitination. Nat. Struct. Biol. 10, 250–255.
Bohacek, R. S., Martin, C., and Guida, W. C. (1996) The art and practice of structure-based drug design: a molecular modeling perspective. Med. Res. Rev. 16, 3–50.
Zhou, X., Wang, X., and Dougherty, E. R. (2003) Construction of genomic networks using mutual-information clustering and reversible-jump Markov chain Monte-Carlo predictor design. Signal Processing 83, 745–761.
Hartemink, A. J., Gifford, D. K., Jaakola, T. S., and Young, R. A. (2001) Using graphical models and genomic expression data to statistically validate models of genetic regulatory networks. Pac. Symp. Biocomput. 422–433.
Shah, N. P., Nicoll, J., Nagar, B., et al. (2002) Multiple BRC-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (ST1571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125.
Shah, N. P., Tran, C., Lee, F. Y., Chen, P., Norris, D., and Sawyers, C. L. (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–4001.
Koonin, E. V. (1999) http://kr.expasy.org/cgi-bin/nicedoc.pl?PDOC0017, last revised July 1999.
Deng, Z., Chuaqui, C., and Singh, J. (2004). Structural interaction fingerprint (SIFt): a novel method for analyzing three-dimensional protein-ligand binding interactions. J. Med. Chem. 47, 337–344.
O’Toole, N., Raymond, S., and Cygler, M. (2003) Coverage of protein sequence space by current structural genomics. J. Struct. Func. Genomics 4, 47–55.
Todorov, N. P. and Dean, P. M. (1997) An evaluation of a method for controlling molecular scaffold diversity in de novo ligand design. J. Comput. Aided Mol. Des. 11, 175–192.
Lloyd, G. G., Garcia-Sosa, A., Alberts, I. L., Todorov, N. P., and Mancera, R. L. (2004) The effect of tightly bound water molecules on the structural interpretation of ligand-derived pharmacophore models. J. Comput. Aided Mol. Des. 18, 89–100.
Mancera, R. L. (2002) De novo ligand design with explicit water molecules: an application to bacterial neuraminidase. J. Comput. Aided Mol. Des. 16, 479–499.
Stahl, M., Todorov, N. P., Tames, T., Mauser, H., Boehm, H.-J., and Dean, P. M. (2002) A validation study on the practical use of de novo design. J. Comput. Aided Motl. Des. 16, 459–478.
Lloyd, D. G., Buenemann, C. L., Todorov, N. P., Manallack, D. T., and Dean, P. M. (2004) Scaffold hopping in de novo drug design—ligand generation in the absence of receptor information. J. Med. Chem. 47, 493–496.
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Dean, P.M. (2005). Computer-Aided Design of Small Molecules for Chemical Genomics. In: Zanders, E.D. (eds) Chemical Genomics. Methods in Molecular Biology™, vol 310. Humana Press. https://doi.org/10.1007/978-1-59259-948-6_3
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DOI: https://doi.org/10.1007/978-1-59259-948-6_3
Publisher Name: Humana Press
Print ISBN: 978-1-58829-399-2
Online ISBN: 978-1-59259-948-6
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