The large numbers of compounds that are now available in drug discovery programmes have resulted in the need for methods to select compounds, both from external suppliers and in combinatorial library design procedures. In this article we describe a method that has been developed for scoring and ranking compounds according to their likelihood of exhibiting activity. The method can be used to determine the order in which compounds should be screened as well as to guide compound acquisition programmes. We then describe a series of experiments we have conducted that explore the benefits of designing combinatorial libraries through an analysis of product space rather than reactant space. The experiments are based on several different diversity metrics and molecular descriptors. We also show how product-based selection allows multi-objectives to be optimised simultaneously, forexample, diversity and physicochemical properties,allowing the design of diverse and drug-like libraries.
This is a preview of subscription content, access via your institution.
Dolle, R.E. and Nelson Jr., K.H., J. Comb. Chem., 1 (1999) 235.
Dean, P.M. and Lewis, R.A. (Eds.), Molecular Diversity in Drug Design, Kluwer Academic Publishers, Dordrecht, 1999.
Willett, P. (Ed.), Computational Methods for the Analysis of Molecular Diversity, Perspectives in Drug Discovery and Design, Vols. 7/8, Kluwer Academic Publishers, Dordrecht, 1997.
Brown, R.D. and Martin, Y.C., J. Chem. Inf. Comput. Sci., 36 (1996) 572.
Brown, R.D. and Martin, Y.C., J. Chem. Inf. Comput. Sci., 37 (1997) 1.
Patterson, D.E., Cramer, R.D., Ferguson, A.M., Clark, R.D. and Weingerger, L.E., J. Med. Chem., 39 (1996) 3049.
Matter, H., J. Med. Chem., 40 (1997) 1219.
Pötter, T. and Matter, H., J. Med. Chem., 41 (1998) 478.
Snarey, M., Terrett, N.K., Willett, P. and Wilton, D.J., J. Mol. Graph. Model, 15 (1997) 372.
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeny, P.J. Adv. Drug Deliv., 23 (1997) 3.
Gillet, V.J., Willett, P. and Bradshaw, J., J. Chem. Inf. Comput. Sci., 38 (1998) 165.
Kier, L.B., Med. Res. Rev., 7 (1987) 417.
CLOGP3 Reference Manual. Daylight Chemical Information Systems, Inc., Mission Viejo, CA, U.S.A.
Daylight Chemical Information Systems, Inc., Mission Viejo, CA, U.S.A.
Goldberg, D.E., Genetic Algorithms in Search, Optimisation, and Machine Learning, Addison-Wesley, Reading, MA, 1989.
The World Drug Index (WDI) is maintained by Derwent Publications Ltd., London.
The SPRESI database is produced by the All-Union Institute of Scientific and Technical Information of the Academy of Science of the USSR (VINITI) in Moscow, and the Central Information Processing for Chemistry (ZIC) in Berlin. It consists of data extracted from approximately 1000 journals, and also patents, books and other sources from 1975-1990. It is distributed by Daylight Chemical Information Systems, Inc., Mission Viejo, CA, U.S.A.
Hann, M., Hudson, B., Lewell, X., Lifely, R., Miller, L. and Ramsden, N., J. Chem. Inf. Comput. Sci., 39 (1999) 897.
Ajay, Walters, W.P. and Murcko, M., J. Med. Chem., 41 (1998) 3314.
Sadowski, J. and Kubinyi, H., J. Med. Chem., 41 (1998) 3325.
Wagener, M. and van Geerestein, V.J., Potential Drugs and Non-drugs: Prediction and Identification of Important Structural Features. Paper presented at the Fifth International Conference on Chemical Structures, The Netherlands, 1996.
The Available Chemicals Directory is available from MDL Information Systems Inc., San Leandro, CA, U.S.A.
Gillet, V.J., Willett, P. and Bradshaw, J., J. Chem. Inf. Comput. Sci., 37 (1997) 731.
Cribbs, C.M., Menius, J.A., Cummins, D. and Young, S.S., Statistical Methods for Monomer Selection in Chemical Library Design. Paper presented at the 211th Meeting of The American Chemical Society, 1996.
Gillet, V.J., Willett, P. and Bradshaw, J., J. Chem. Inf. Comput. Sci., 39 (1999) 169.
UNITY is available from Tripos Inc., St. Louis, MO, U.S.A.
Molconn-Z is available from eduSoft, Ashland, VA, U.S.A.
Lajiness, M.S., Perspect. Drug Discov. Design, 7/8 (1997) 65.
Holliday, J.D., Ranade, S.S. and Willett, P., Quant. Struct.-Act. Relat., 14 (1995) 501.
Watson, S., Solution Phase Synthesis of Libraries Based on Thiazole Templates. 3rd Annual Random and Rational Conference, Geneva, Strategic Research Institute, New York, NY, 1996.
Jamois, E.A., Evaluation of Reagent-based and Product-based Strategies in the Design of Combinatorial Subsets, Paper presented at the 217thMeeting of The American Chemical Society, 1999.
Pearlman, R.S. and Smith, K.M., Novel Algorithms for the Design of Diverse and Focused Combinatorial Libraries, Paper presented at the 217th Meeting of The American Chemical Society, 1999.
About this article
Cite this article
Gillet, V.J., Nicolotti, O. Evaluation of reactant-based and product-based approaches to the design of combinatorial libraries. Perspectives in Drug Discovery and Design 20, 265–287 (2000). https://doi.org/10.1023/A:1008797526431
- bioactivity profiles
- combinatorial library design
- product-based selection
- reactant-based selection