toward a better drug classification

Just a bit of self-promotion about my last paper. Despite the superiority of longitudinal vs cross-sectional studies, the dynamics of drug action are poorly explored in pre-clinical studies. Little is known about how drugs affect the activity of their intended target over time. Here, we used a longitudinal imaging approach to accurately follow the state of transcriptional activity of one drug target (the estrogen receptor) in 8 anatomical areas of living ERE-luc reporter mice over 21 consecutive days of hormone replacement therapy with 10 different Selective Estrogen Receptor Modulators (SERMs).

This is a 2006 shot: I checked the accuracy of the algorithm to measure the area under the curve by weighing small pieces of paper. My bench-mates are still laughing...

We found that each SERM caused tissue-specific oscillations on ER transcriptional activity which were predictive of the drug structure (after rational extraction of meaningful molecular descriptors).

For more than one century, the measure of drug structure-activity relationships has been based on mathematical equations describing the interaction of the drug with its biological receptor. This is now obsolete, as 'binding' does not necessarily spell 'function'. Here, a systematic study of spatio-temporal effects is proposed as a measure of drug efficacy for the classification of pharmacologically active compounds.

We conclude that the use of reporter mouse facilitates the identification of SERMs able to mimic the physiological estrous cycle and anticipates the possibility of a reverse approach in medicinal chemistry where the space-temporal plot of target activity drives the identification of subtle structure-activity relationships.

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Rando, G., Horner, D., Biserni, A., Ramachandran, B., Caruso, D., Ciana, P., Komm, B., & Maggi, A. (2010). An Innovative Method to Classify SERMs Based on the Dynamics of Estrogen Receptor Transcriptional Activity in Living Animals Molecular Endocrinology, 24 (4), 735-744 DOI: 10.1210/me.2009-0514
Rando G, Biserni A, Ciana P, & Maggi A (2010). Profiling of drug action using reporter mice and molecular imaging. Methods in molecular biology (Clifton, N.J.), 602, 79-92 PMID: 20012393
Rando G, Arca S, Casiraghi E, Campadelli P & Maggi A (2009). Automatic Segmentation of Mouse Images. Proc 10th European Congress of International Society for Stereology, Bologna, Italy, 2009 link: abstract