The Signature molecular descriptor [1] is a powerful tool to aid in molecular design, where the ultimate goal is to develop a focused database of compounds well suited for a particular application. Ideally one would like to examine potential compounds outside the current databases. Here a novel algorithm is available to achieve that objective by solving the inverse quantitative-structure activity relationship (I-QSAR) problem. Solutions are obtained by generating and solving a system of Diophantine (integer coefficients and solutions) equations based on valence and consistency constraints for a particular dataset. This approach is more efficient than merely modifying substituent groups around a given scaffold, and non-intuitive structures can be created. The solutions are filtered via a QSAR to only consider those with favorable property predictions. Signature has previously been successful at solving the I-QSAR problem. [2,3] In this study, we explore the I-QSAR technique to develop Cyclooxygenase-2 (COX-2) inhibitors for potential replacement of Celebrex and Vioxx because of unwanted cardiovascular side effects.

Two datasets of COX-2 inhibitors and their corresponding biological activities were obtained from the literature based on the type of biological cell tested. The Chinese hamster ovary (CHO) set contained 56 compounds, and the human whole blood (HWB) set provided 29. The I-QSAR problem was solved separately for each set. The overall I-QSAR process, QSAR statistics, and new compounds with stronger activities than those in the original datasets will be presented. Approximately 100 potential replacement compounds were identified and the highest-quality candidates will be reported.

[1] D. Visco Jr., R. Pophale, M. Rintoul, J. L. Faulon, “Developing a methodology for an inverse quantitative structure-activity relationship using the signature molecular descriptor”, J. of Molecular graphics and Modeling, 20, 429-438 (2002).

[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).