Quantitative structure-activity relationships (QSARs) provide a description of the correlation between the structure of a molecule and a specific molecular property of interest. QSARs can be employed to refine the search for molecules matching a desired property in an existing database, but ideally one would like to examine potential compounds outside the database through solving the inverse-QSAR (I-QSAR) problem. Signature is a powerful molecular descriptor [1] with previous success in solving the I-QSAR problem. [2,3] Focused libraries of compounds with desired predicted values are created from which a high-quality lead compound can be developed. In this study, we explore the I-QSAR technique to develop inhibitors of phosphate cdc25B.

Cdc25 phosphates play an important role in the growth and development of eukaryotic cells. In humans, there are three varieties known as cdc25A, B, and C. Cdc25B is often over-expressed in various forms of cancer including lung, breast, and prostate. Blocking the cdc25b with chemical inhibitors has the potential to interfere with tumor cells. A database of 28 known cdc25B inhibitors with IC50 data was obtained to create a QSAR. From this set, the inverse QSAR technique was employed to generate potent cdc25B inhibitors outside of the original 28 compounds.

[1] J. F. Faulon, D. P. Visco, Jr. and R. S. Pophale, “The Signature Molecular Descriptor. 1. Extended Valence Sequences vs. Topological Indices in QSAR and QSPR studies”, J. Chem. Inf. Comput. Sci., 43, 707 – 720 (2003).

[2] C. Churchwell, M. D. Rintoul, S. Martin, D. P. Visco, Jr., A. Kotu, R. S. Larson, L.O. Sillerud, D. C. Brown and J. L. Faulon , “The Signature Molecular Descriptor. 3. Inverse Quantitative Structure-Activity Relationship of ICAM-1 Inhibitory Peptides”, J Molecular Graphics and Modelling, 22, 263 – 273 (2004).

[3] D. Weis, J. L. Faulon, R. LeBorne, D. Visco, “The Signature Molecular Descriptor. 5. The Design of Hydrofluoroether Foam Blowing Agents Using Inverse-QSAR”, Ind. Eng. Chem. Res, 44, 8883-8891 (2005).