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Park, Hwangseo,Park, So Ya,Nam, Sang-Won,Ryu, Seong Eon SAGE Publications 2014 Journal of biomolecular screening Vol.19 No.10
<P>Recently, dual-specificity phosphatase 16 (DUSP16) emerged as a promising therapeutic target protein for the development of anti-atherosclerosis and anticancer medicines. The present study was undertaken to identify the novel inhibitors of DUSP16 based on the structure-based virtual screening. We have been able to find seven novel inhibitors of DUSP16 through the drug design protocol involving homology modeling of the target protein, docking simulations between DUSP16 and its putative inhibitors with the modified scoring function, and in vitro enzyme assay. These inhibitors revealed good potency, with IC<SUB>50</SUB> values ranging from 1 to 22 µM, and they were also screened computationally for having desirable physicochemical properties as drug candidates. Therefore, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory activity against DUSP16. Structural features relevant to the stabilization of the newly identified inhibitors in the active site of DUSP16 are addressed in detail.</P>
Structure-based <i>de novo</i> design and identification of D816V mutant-selective c-KIT inhibitors
Park, Hwangseo,Lee, Soyoung,Lee, Suhyun,Hong, Sungwoo The Royal Society of Chemistry 2014 Organic & Biomolecular Chemistry Vol.12 No.26
<P>To identify potent and selective inhibitors of D816V, the most common gain-of-function c-KIT mutant, we carried out structure-based <I>de novo</I> design using 7-azaindole as the core and the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of new c-KIT inhibitors specific for the D816V mutant. The 3-(3,4-dimethoxyphenyl)-7-azaindole scaffold was optimized and represents a lead structure for the design of the potent and specific inhibitors of the D816V mutant. The results of molecular dynamics simulations indicate that hydrogen bonding interactions between the 7-azadindole moiety and the backbone groups of Cys673 are the most significant determinant for the potency and selectivity of c-KIT inhibitors.</P> <P>Graphic Abstract</P><P>New 7-azaindole-based c-KIT inhibitors with nanomolar inhibitory activity and high selectivity for the gain-of-function D816V mutant were identified through the structure-based <I>de novo</I> design using the scoring function improved by implementing an accurate solvation free energy. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4ob00053f'> </P>
Park, Hwangseo,Hong, Seunghee,Kim, Jinhee,Hong, Sungwoo American Chemical Society 2013 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.135 No.22
<P>Although the constitutively activated break-point cluster region–Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme–inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2013/jacsat.2013.135.issue-22/ja311756u/production/images/medium/ja-2012-11756u_0013.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja311756u'>ACS Electronic Supporting Info</A></P>
Park, Hwangseo,Jung, Suk‐,Kyeong,Yu, Keum R.,Kim, Ju H.,Kim, Yong‐,Sam,Ko, Jeong H.,Park, Byoung C.,Kim, Seung J. Blackwell Publishing Ltd 2011 Chemical biology & drug design Vol.78 No.4
<P>Despite a series of persuasive experimental evidence for the involvement of eyes absent protein tyrosine phosphatases in various human cancers, no small‐molecule inhibitor has been reported so far. We have identified seven novel inhibitors of eyes absent homologue 2 (Eya2) with IC<SUB>50</SUB> values ranging from 1 to 70 μ<SMALL>m</SMALL> by the virtual screening with docking simulations and enzyme inhibition assay. Atomic charges of the active‐site Mg<SUP>2+</SUP> ion complex are calculated to enhance the accuracy of docking simulations. The newly discovered inhibitors are structurally diverse and have various chelating groups for the Mg<SUP>2+</SUP> ion. The interactions with the amino acid residues responsible for the stabilizations of the inhibitors in the active site of Eya2 are addressed in detail.</P>
Park, Hwangseo,Jeon, Young Ho Springer 2008 JOURNAL OF MOLECULAR MODELING Vol.14 No.9
<P>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. As a method for the discovery of novel inhibitors of Cdc25 phosphatases, we have evaluated the computer-aided drug design protocol involving the homology modeling of Cdc25A and virtual screening with the two docking tools: FlexX and the modified AutoDock program implementing the effects of ligand solvation in the scoring function. The homology modeling with the X-ray crystal structure of Cdc25B as a template provides a high-quality structure of Cdc25A that enables the structure-based inhibitor design. Of the two docking programs under consideration, AutoDock is found to be more accurate than FlexX in terms of scoring putative ligands. A detailed binding mode analysis of the known inhibitors shows that they can be stabilized in the active site of Cdc25A through the simultaneous establishment of the multiple hydrogen bonds and the hydrophobic interactions. The present study demonstrates the usefulness of the modified AutoDock program as a docking tool for virtual screening of new Cdc25 phosphatase inhibitors as well as for binding mode analysis to elucidate the activities of known inhibitors.</P>