ACB Blocks' Fragment Library

We have recently finished designing a special NMR-directed fragment library of 1280 small drug-like compounds fitting strict NMR-&-Ro3 fragment criteria. Listed below are the basic characteristics of the resulted product:

1. All compounds are drug-like privileged structures. The selection of such specific fragments was based on the methodology of identification of privileged substructures.

2. The compounds are highly diverse, especially in the sense of "heterocyclicdiversity. Each compound may be used as a precursor for building up sub-libraries that can be explored in further experiments. *

3. There are several dispersed proton signals in the NMR spectrum of each compound and all structures are stereo-defined.

4. All compounds satisfy Ro3 criteria:

  • Compounds are small - MW <300 (Ro3: MW < 330), average MW=214

    • Compounds typically have:
  • 1-3 rings (Ro3: < 3);
  • 1-5 rotatable bonds (Ro3: < 6), average 2.16
  • 1-3 donors of hydrogen bonds (Ro3: < 3), average 1.66
  • 1-5 acceptors of hydrogen bonds (Ro3: between 1 and 6), average 3.03

    		•


    Molecular weight


    LogP


    LogSw


    Number of rotatable bonds


    Number of hydrogen bond donors


    Number of hydrogen bond acceptors

    5. Compounds are non-aggregative.

    6. Purity of fragments is more than 96% (LCMS, NMR).

    7. Compounds are non-reactive. About 100 special filters were applied for elimination of compounds with unwanted functionality (NO2, SH, hydrazones, epoxides, alkylating agents, Michael acceptors, redox, etc.)

    8. Compounds are polar and non-lipophylic. ClogP < 5.0 for all the selected compounds (average 2.03) and for 958 compounds ClogP < 3.0 (Ro3: ClogP < 3.0). These results are obtained with ALOGPC program. **, ***

    9. Compounds should prove soluble in D2O. Solubility predicted with ALOGPC software seems very promising, as all compounds have ClogSW > -5.00; 1150 compounds have ClogSW > - 4.00; for 808 compounds the calculated solubility is more than 1.0 mM (ClogSW > -3.00).

    We expect the proposed library to be an extremely powerful tool for NMR / X-Ray / MS-based drug discovery.

    * N. Baurin, F. Aboul-Ela, X. Barril, B. Davis, M. Drysdale, B. Dymock, H. Finch, C. Fromont, C. Richardson, H. Simmonite, R.E. Hubbard J. Chem. Inf. Comput. Sci. 2004, 44, 2157-2166.
    ** I. Tetko, P. Bruneau Journal of Pharmaceutical Sciences, 2004, v. 93, 12, 3103-3110
    *** Igor V. Tetko, and Gennadiy I. Poda J. Med. Chem. 2004, 47, 5601-5604

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