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Park, Hwangseo,Chi, Okyung,Kim, Jinhee,Hong, Sungwoo American Chemical Society 2011 JOURNAL OF CHEMICAL INFORMATION AND MODELING Vol.51 No.11
<P>Tropomyosin-related kinase A (TrkA) is a promising target for the development of cancer and pain therapeutics. Here, we report the first successful example of the use of a structure-based virtual screening to identify novel TrkA inhibitors. The accuracy of the virtual screening was improved by introducing an accurate solvation free energy term into the original AutoDock scoring function. We applied a drug design protocol involving homology modeling, docking analysis of a large chemical library, and enzyme inhibition assays to identify six structurally diverse TrkA inhibitors with <I>K</I><SUB><I>d</I></SUB> values ranging from 3 to 40 μM. The significant potencies and good physicochemical properties of these drug candidates strongly support their consideration in a development effort that would involve structure–activity relationship (SAR) studies to optimize the inhibitory activities. We also addressed the structural and energetic features associated with binding of the newly identified inhibitors in the ATP-binding site of TrkA. The results indicate that any structural modifications introduced for the purpose of enhancing the activity of TrkA inhibitors should maximize the attractive interactions within the ATP-binding site and simultaneously minimize the desolvation cost for complexation.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jcisd8/2011/jcisd8.2011.51.issue-11/ci200378s/production/images/medium/ci-2011-00378s_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ci200378s'>ACS Electronic Supporting Info</A></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,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>
Park, Woon Bae,Kim, Hyunmin,Park, Hwangseo,Yoon, Chulsoo,Sohn, Kee-Sun American Chemical Society 2016 Inorganic Chemistry Vol.55 No.5
<P>A Ca1.5Ba0.5Si5O3N6:Eu2+ phosphor with a monoclinic lattice in the Cm space group exhibiting a composite structure consisting of CaSi2O2N2-like and BaSi6N8O-like structures was examined in terms of structure and luminescence. The luminescent properties of the Ca1.5Ba0.5Si5O3N6:Eu2+ phosphor could be suitable for light emitting diode applications since it exhibited a promising yellow (or amber) emission peaking at similar to 570-590 nm at excitations of 450-460 nm. The present investigation was focused on verifying the composite structure by employing quantum mechanical calculations such as the Hartree-Fock ab initio calculation and a density functional theory calculation along with precise structural and compositional analyses. The two-peak emission behavior ascribed to the composite structure was also examined in terms of continuous wave time-resolved In addition, the energy and photoluminescence. transfer between two activator sites ascribed to the composite structure was examined in detail.</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>