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Discovery of Novel DUSP4 Inhibitors through the Virtual Screening with Docking Simulations
박황서,전태진,Pham Ngoc Chien,So Ya Park,Sung Min Oh,김승준,류성언 대한화학회 2014 Bulletin of the Korean Chemical Society Vol.35 No.9
Dual specificity protein phosphatase 4 (DUSP4) has been considered a promising target for the development of therapeutics for various human cancers. Here, we report the first example for a successful application of the structure-based virtual screening to identify the novel small-molecule DUSP4 inhibitors. As a consequence of the virtual screening with the modified scoring function to include an effective molecular solvation free energy term, five micromolar DUSP4 inhibitors are found with the associated IC50 values ranging from 3.5 to 10.8 μM. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they may serve as a starting point of the structure-activity relationship study to optimize the medical efficacy. Structural features relevant to the stabilization of the new inhibitors in the active site of DUSP4 are discussed in detail.
박황서,Jeong-Yi Jeon,류성언 대한화학회 2012 Bulletin of the Korean Chemical Society Vol.33 No.11
Mitogen-activated protein kinase phosphatase 4 (MKP4) has proved to be a promising target for the development of therapeutics for the treatment of diabetes and the other metabolic diseases. Here, we report an example for a successful application of the structure-based virtual screening to identify three novel inhibitors of MKP4. These inhibitors have desirable physicochemical properties as a drug candidate and reveal a moderate potency with IC50 values ranging from 4.9 to 32.3 μM. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory and antidiabetic activities. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of MKP4 are discussed in detail.
박황서,Suk-Kyeong Jung,Young Jae Bahn,Dae Gwin Jeong,류성언,김승준 대한화학회 2009 Bulletin of the Korean Chemical Society Vol.30 No.6
Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapy due to the correlation of their overexpression with a wide variety of cancers. We have been able to identify five novel Cdc25 phosphatase inhibitors with micromolar activity by means of a structure-based de novo design method with a known inhibitor scaffold. Because the newly discovered inhibitors are structurally diverse and have desirable physicochemical properties as a drug candidate, they deserve further investigation as anticancer drugs. The differences in binding modes of the identified inhibitors in the active sites of Cdc25A and B are addressed in detail.