Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH FRONT

Is There a Single ‘Best Pool’ of Commercial Reagents To Use in Combinatorial Library Design To Conform to a Desired Product–Property Profile?

Jean-François Truchon A B and Christopher I. Bayly A
+ Author Affliations
- Author Affliations

A Merck Frosst Canada & Co., 16711 Trans Canada Hwy, Kirkland, Québec H9H 3L1, Canada.

B Corresponding author. Email: jeanfrancois_truchon@merck.com

Australian Journal of Chemistry 59(12) 879-882 https://doi.org/10.1071/CH06139
Submitted: 29 April 2006  Accepted: 22 July 2006   Published: 20 December 2006

Abstract

A novel computer algorithm for library design in combinatorial chemistry, GLARE (Global Library Assessment of Reagent), is used to select an optimal subset of reagents in two related libraries according to the Lipinski rule of five applied to the products. The optimized libraries show excellent compliance with the desired profiles although the original huge libraries do not. Then we show, using ten different virtual libraries, that (a) a relatively small fraction of commercially available reagents is of general use in drug/lead-like combinatorial chemistry and (b) that between 10 and 20% of the reagents are not of general use but specific to a library. This demonstrates the utility of using a product-based reagent selection method.


References


[1]   A. R. Leach, M. M. Hann, Drug Discov. Today 2000, 5,  326.
        | CrossRef |   open url image1

[2]   (a) G. Chen, S. Zheng, X. Luo, J. Shen, W. Zhu, H. Liu, C. Gui, J. Zhang, M. Zheng, C. M. Puah, K. Chen, H. Jiang, J. Comb. Chem. 2005, 7,  398.
        | CrossRef |   open url image1
       (b) J. A. H. Lainton, M. C. Allen, M. Burton, S. Cameron, T. R. G. Edwards, G. Harden, R. Hogg, W. Leung, S. Miller, J. J. Morrish, S. M. Rooke, B. Wendt, J. Comb. Chem. 2003, 5,  400.
        | CrossRef |   open url image1

[3]   MDL Available Chemicals Directory (Elsevier MDL: San Ramon, CA). This database contains more than 480000 unique substances made available by more than 670 suppliers. www.mdl.com

[4]   (a) V. J. Gillet, W. Khatib, P. Willet, P. J. Fleming, D. V. S. Green, J. Chem. Inf. Comput. Sci. 2002, 42,  375.
        | CrossRef |   open url image1
       (b) G. Bravi, D. V. S. Green, M. M. Hann, A. R. Leach, J. Chem. Inf. Comput. Sci. 2000, 40,  1441.
        | CrossRef |   open url image1
       (c) R. D. Cramer, D. E. Patterson, R. D. Clark, F. Soltanshahi, M. S. Lawless, J. Chem. Inf. Comput. Sci. 1998, 38,  1010.
        | CrossRef |   open url image1
       (d) R. V. Stanton, J. Mount, J. L. Miller, J. Chem. Inf. Comput. Sci. 2000, 40,  701.
        | CrossRef |   open url image1

[5]   (a) J.-F. Truchon, C. I. Bayly, J. Chem. Inf. Model. 2006, 46,  1536.
        | CrossRef |   open url image1
       (b) From ref. [5a], Lib01 to Lib09 and Lib12 are used where the amines of Lib01, the aldehydes of Lib02, the carboxylic acids of Lib09 and the alcohols of Lib03 are chosen as initial reagent lists in all libraries where needed.
       (c) In all cases, the scaled pruning parameter α was set to 6.0 and the minimum partition size was set to 16 as suggested in ref. [5a].

[6]   C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv. Drug Deliv. Rev. 1997, 23,  3.
        | CrossRef |   open url image1

[7]   G. Klopman, J.-Y. Li, S. Wang, M. Dimayuga, J. Chem. Inf. Comput. Sci. 1994, 18,  478.
         open url image1

[8]   B. P. Feuston, S. J. Chakravorty, J. F. Conway, J. C. Culberson, J. Forbes, B. Kraker, P. A. Lennon, C. Lindsley, G. B. McGaughey, R. Mosley, R. B. Sheridan, M. Valenciano, S. K. Kearsley, Curr. Top. Med. Chem. 2005, 5,  773.
        | CrossRef |   open url image1

[9]   J. M. Cobb, N. Grimster, N. Khan, J. Y. Q. Lai, H. J. Payne, L. J. Payne, T. Raynham, J. Taylor, Tetrahedron Lett. 2002, 43,  7557.
        | CrossRef |   open url image1



Rent Article (via Deepdyve) Export Citation