In silico identification and in vivo characterization of small molecule therapeutic hypothermia mimetics

• DOI: 10.1016/j.bmc.2017.10.039
• Publication Date: 2017-10-31T19:17:02Z
• Authors: Claire Coderch; María Díaz de Cerio; Jose María Zapico; Rafael Peláez; Ignacio M. Larrayoz; Ana Ramos; Alfredo Martínez; Beatriz de Pascua...
• Keywords: Male; Models, Molecular; 0301 basic medicine; Dose-Response Relationship, Drug; Molecular Structure; RNA-Binding Proteins; Hypothermia; Cell Line; High-Throughput Screening Assays; Rats; 3. Good health; Small Molecule Libraries; Structure-Activity Relationship; 03 medical and health sciences; Cold Shock Proteins and Peptides; Animals

Hypothermia has been proved to have a beneficial effect on several pathologies. CIRBP is one of the so termed cold-shock proteins involved in this process. In this work, we have detected small molecules capable of modulating the activity of CIRBP in the absence of a cold stimulus, by High Throughput Virtual Screening (HTVS) of the Diversity Set IV of the NCI and 15 compounds of our in-house data base. Fifteen compounds were selected from the HTVS to carry out a second screening through a cell-based Western blot assay. This assay, together with molecular modeling studies allowed us to select compound zr17-2 for an in vivo experiment, which showed an interesting increase of CIRBP expression in several organs of experimental animals. Therefore, we have demonstrated that the effect of hypothermia can be mimicked by small molecules, which can be developed as first-in-class new drugs for the treatment of several diseases.