Structure-based de novo design and synthesis of aminothiazole-based p38 MAP kinase inhibitors

p38 mitogen-activated protein kinase (MAPK) is a promising target for the development of therapeutics for various immunological diseases. We designed and synthesized aminothiazole-based p38 MAPK inhibitors of with IC50 values ranging from 0.1 to 2 μM by means of the structure-based de novo design of phenyl-(2-phenylamino-thiazol-5-yl)-methanone scaffold. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anti-inflammatory drugs. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are discussed in detail.

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