Enamine's Hinge Region Directed Kinase Platform

Protein kinases are evidently the most exploited target in modern drug discovery. All known kinase inhibitors - ATP-competitive binders bind at the hinge region, a common structural motif of all kinases. Development of the library of compounds which bind the hinge region of kinases could become a powerful platform for further quest for binders to specific kinase targets.

Hinge-region-directed Kinase Platform was developed based on the Enamine’s Real DataBase (currently over 12 million structures). First, Lipinsky, Veber rules, and more than 80 MedChem structural filters, allowing to exclude structures with reactive groups and potential nonselective toxicity, were applied to obtain the Drug-Like Collection (4,013,473 structures). Then, 3D-structures of kinase-inhibitor complexes and binding interactions in the active site of the known ATP-competitive inhibitors were analyzed. It was revealed that at least two hydrogen bonds with the hinge-region were necessary to exhibit high inhibitor affinity.

Finally, molecular fragments that were able to form at least two hydrogen bonds with Hinge-region were analyzed and structural 2D filters were created. The entire Drug-Like Enamine’s Real DataBase was filtered according to 2D Hinge-region-directed Filtersto obtain Hinge-region-directed Kinase Platform (906,698 structures). These structures represent novel compounds which have never been screened for biological activity yet, and therefore, bear high potential of chemical diversity and patentability. The success of the newly developed filtering procedure can be demonstrated by the fact that the same procedure, applied to the stock collection, yielded a set of “bestseller” compounds (sold better than average).