ABSTRACT

The p90 ribosomal S6 kinases (RSK) are a family of serine/threonine protein kinases and are shown to be involved in cancer cell proliferation. The lack of highly selective inhibitors and also the lack of structural information regar-ding the mechanism of those inhibitors restricts the progress in this field. It has also been reported that without a proper crystal structure of RSK, the protein-inhibitor interactions in silico studies had been erroneously concluded. The first e-pharmacophore model for RSK2 has been generated in this study using recently resolved high resolu-tion crystal structure of RSK2 in complex with LJH685 that is amongst the most potent and selective RSK inhibitors to date. 12 compounds have been suggested as promising potent and selective RSK inhibitors after the combina-tion of virtual screening of a large database (ca. 7 million compounds with more than 144 million conformations), followed by a series of molecular docking work flow and visual inspection of all hits for critical binding modes. Amongst those hits, 5777208 and 5919607 have been found to have remarkable docking score and binding interac-tions.