In silico Screening for Signalosome Inhibitors

Introduction The COP9 signalosome (CSN), a multi enzyme complex, is involved in cell cycle regulation. CSN possesses kinase activity that phosphorylates proteins such as p53 and c-Jun [1] and is therefore an interesting therapeutic target for anti-tumor drugs. There are known inhibitors (e.g. Curcurmin) of the kinase activity associated with the signalosome but they exhibit low binding constants and specificity. Using them we have carried out a 3D similarity screening for our in-house database of about 106 available organic compounds. The superposition procedure is very fast enabling the explicit consideration of conformers reflecting the structural flexibility. Upon selection we used a number of property filters to achieve drug-like lead compound [2]. First experimental tests show significant improvement of inhibition.