Use of a fluorescent polarization based high throughput assay to identify new calmodulin ligands.

In order to develop a fluorescence polarization (FP) assay for calcium binding proteins, a fluorescent peptides based library of 1328 compounds has been synthesized. The use of this library has been validated by setting up a FP-high-throughput screening (FP-HTS) assay for calmodulin using the synthetic gene product (synCaM). With this assay, a set of 880 FDA approved compounds was screened. Besides the promazine class, we discovered two new classes of compounds that interact with calmodulin in a calcium dependent manner. One class has compounds with anti-histaminic/spasmolytic activities, and the other one are detergents with antibacterial activities.

Similarity in drugs: reflections on analogue design.

A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues).

Selective optimization of side activities: the SOSA approach.

Selective optimization of side activities of drug molecules (the SOSA approach) is an intelligent and potentially more efficient strategy than HTS for the generation of new biological activities. Only a limited number of highly diverse drug molecules are screened, for which bioavailability and toxicity studies have already been performed and efficacy in humans has been confirmed. Once the screening has generated a hit it will be used as the starting point for a drug discovery program. Using traditional medicinal chemistry as well as parallel synthesis, the initial 'side activity' is transformed into the 'main activity' and, conversely, the initial 'main activity' is significantly reduced or abolished. This strategy has a high probability of yielding safe, bioavailable, original and patentable analogues.

Prednisone reduces muscle degeneration in dystrophin-deficient Caenorhabditis elegans.

Duchenne muscular dystrophy is a degenerative muscular disease caused by mutations in the dystrophin gene. There is no curative treatment against Duchenne muscular dystrophy. In several countries, the steroid prednisone (or analogs) is prescribed as a palliative treatment. In the model animal Caenorhabditis elegans, mutations of the dys-1 dystrophin-like gene lead to a muscular degenerative phenotype when they are associated with a mild MyoD mutation. This cheap and fast-growing model of dystrophinopathy may be used to screen for molecules able to slow muscle degeneration. In a blind screen of approximately 100 compounds covering a wide spectrum of targets, we found that prednisone is beneficial to the C. elegans dystrophin-deficient muscles. Prednisone reduces by 40% the number of degenerating cells in this animal. This result is a proof-of-principle for the use of C. elegans as a tool in the search for molecules active against the effects of dystrophin-deficiency. Moreover, since C. elegans is not susceptible to inflammation, this suggests that prednisone exerts a direct effect on muscle survival.