Publications by authors named "Hwangseo Park"

99 Publications

Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer.

Int J Mol Sci 2020 Dec 7;21(23). Epub 2020 Dec 7.

Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea.

Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 10-fold selectivity in the inhibition of EGFR over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFR and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFR inhibitors were actually made possible by virtue of the modified protein-ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.
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http://dx.doi.org/10.3390/ijms21239323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730458PMC
December 2020

Kinase and GPCR polypharmacological approach for the identification of efficient anticancer medicines.

Org Biomol Chem 2020 Oct;18(41):8402-8413

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. and Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.

Discovery of an anticancer medicine using a single target protein has often been unsuccessful due to the complexity of pathogenic mechanisms as well as the presence of redundant signaling pathways. In this work, we attempted to find promising anticancer drug candidates by simultaneously targeting casein kinase 1 delta (CK1δ) and muscarinic acetylcholine receptor M3 (M3R). Through the structure-based virtual screening and de novo design with the modified potential function for protein-ligand binding, a series of benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2-amine (BITA) derivatives were identified as CK1δ inhibitors and also as M3R antagonists. The biochemical potencies of these bifunctional molecules reached the nanomolar and low-micromolar levels with respect to CK1δ and M3R, respectively. A common interaction feature in the calculated CK1δ-inhibitor and M3R-antagonist complexes is that the BITA moiety is well-stabilized in the orthosteric site of M3R and the hinge region of CK1δ through the establishment of the three hydrogen bonds and the hydrophobic contacts in the vicinity. The computational and experimental results found in this work exemplify the efficiency of kinase and GPCR polypharmacology in developing anticancer medicines.
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http://dx.doi.org/10.1039/d0ob01917hDOI Listing
October 2020

Development of A4 antibody for detection of neuraminidase I223R/H275Y-associated antiviral multidrug-resistant influenza virus.

Nat Commun 2020 07 9;11(1):3418. Epub 2020 Jul 9.

Bionanotechnology Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.

The emergence and spread of antiviral drug-resistant viruses have been a worldwide challenge and a great concern for patient care. We report A4 antibody specifically recognizing and binding to the mutant I223R/H275Y neuraminidase and prove the applicability of A4 antibody for direct detection of antiviral multidrug-resistant viruses in various sensing platforms, including naked-eye detection, surface-enhanced Raman scattering-based immunoassay, and lateral flow system. The development of the A4 antibody enables fast, simple, and reliable point-of-care assays of antiviral multidrug-resistant influenza viruses. In addition to current influenza virus infection testing methods that do not provide information on the antiviral drug-resistance of the virus, diagnostic tests for antiviral multidrug-resistant viruses will improve clinical judgment in the treatment of influenza virus infections, avoid the unnecessary prescription of ineffective drugs, and improve current therapies.
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http://dx.doi.org/10.1038/s41467-020-17246-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347576PMC
July 2020

Graphite as a Long-Life Ca-Intercalation Anode and its Implementation for Rocking-Chair Type Calcium-Ion Batteries.

Adv Sci (Weinh) 2019 Dec 16;6(24):1902129. Epub 2019 Oct 16.

Department of Printed Electronics Engineering Sunchon National University Suncheon Chonnam 57922 Republic of Korea.

Herein, graphite is proposed as a reliable Ca-intercalation anode in tetraglyme (G). When charged (reduced), graphite accommodates solvated Ca-ions (Ca-G) and delivers a reversible capacity of 62 mAh g that signifies the formation of a ternary intercalation compound, Ca-G·C. Mass/volume changes during Ca-G intercalation and the evolution of in operando X-ray diffraction studies both suggest that Ca-G intercalation results in the formation of an intermediate phase between stage-III and stage-II with a gallery height of 11.41 Å. Density functional theory calculations also reveal that the most stable conformation of Ca-G has a planar structure with Ca surrounded by G, which eventually forms a double stack that aligns with graphene layers after intercalation. Despite large dimensional changes during charge/discharge (C/D), both rate performance and cyclic stability are excellent. Graphite retains a substantial capacity at high C/D rates (e.g., 47 mAh g at 1.0 A g s vs 62 mAh g at 0.05 A g) and shows no capacity decay during as many as 2000 C/D cycles. As the first Ca-shuttling calcium-ion batteries with a graphite anode, a full-cell is constructed by coupling with an organic cathode and its electrochemical performance is presented.
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http://dx.doi.org/10.1002/advs.201902129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918123PMC
December 2019

Structural basis for recognition of the tumor suppressor protein PTPN14 by the oncoprotein E7 of human papillomavirus.

PLoS Biol 2019 07 19;17(7):e3000367. Epub 2019 Jul 19.

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

Human papillomaviruses (HPVs) are causative agents of various diseases associated with cellular hyperproliferation, including cervical cancer, one of the most prevalent tumors in women. E7 is one of the two HPV-encoded oncoproteins and directs recruitment and subsequent degradation of tumor-suppressive proteins such as retinoblastoma protein (pRb) via its LxCxE motif. E7 also triggers tumorigenesis in a pRb-independent pathway through its C-terminal domain, which has yet been largely undetermined, with a lack of structural information in a complex form with a host protein. Herein, we present the crystal structure of the E7 C-terminal domain of HPV18 belonging to the high-risk HPV genotypes bound to the catalytic domain of human nonreceptor-type protein tyrosine phosphatase 14 (PTPN14). They interact directly and potently with each other, with a dissociation constant of 18.2 nM. Ensuing structural analysis revealed the molecular basis of the PTPN14-binding specificity of E7 over other protein tyrosine phosphatases and also led to the identification of PTPN21 as a direct interacting partner of E7. Disruption of HPV18 E7 binding to PTPN14 by structure-based mutagenesis impaired E7's ability to promote keratinocyte proliferation and migration. Likewise, E7 binding-defective PTPN14 was resistant for degradation via proteasome, and it was much more effective than wild-type PTPN14 in attenuating the activity of downstream effectors of Hippo signaling and negatively regulating cell proliferation, migration, and invasion when examined in HPV18-positive HeLa cells. These results therefore demonstrated the significance and therapeutic potential of the intermolecular interaction between HPV E7 and host PTPN14 in HPV-mediated cell transformation and tumorigenesis.
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http://dx.doi.org/10.1371/journal.pbio.3000367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668832PMC
July 2019

Synthesis and biological evaluation of acylthiourea against DUSP1 inhibition.

Bioorg Med Chem Lett 2019 07 14;29(14):1746-1748. Epub 2019 May 14.

Anticancer Agent Research Center, KRIBB, Cheongju 28116, Republic of Korea. Electronic address:

Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition.
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http://dx.doi.org/10.1016/j.bmcl.2019.05.021DOI Listing
July 2019

Development and application of a comprehensive machine learning program for predicting molecular biochemical and pharmacological properties.

Phys Chem Chem Phys 2019 Feb;21(9):5189-5199

Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul 05006, Korea.

We establish a comprehensive quantitative structure-activity relationship (QSAR) model termed AlphaQ through the machine learning algorithm to associate the fully quantum mechanical molecular descriptors with various biochemical and pharmacological properties. Preliminarily, a novel method for molecular structural alignments was developed in such a way to maximize the quantum mechanical cross correlations among the molecules. Besides the improvement of structural alignments, three-dimensional (3D) distribution of the molecular electrostatic potential was introduced as the unique numerical descriptor for individual molecules. These dual modifications lead to a substantial accuracy enhancement in multifarious 3D-QSAR prediction models of AlphaQ. Most remarkably, AlphaQ has been proven to be applicable to structurally diverse molecules to the extent that it outperforms the conventional QSAR methods in estimating the inhibitory activity against thrombin, the water-cyclohexane distribution coefficient, the permeability across the membrane of the Caco-2 cell, and the metabolic stability in human liver microsomes. Due to the simplicity in model building and the high predictive capability for varying biochemical and pharmacological properties, AlphaQ is anticipated to serve as a valuable screening tool at both early and late stages of drug discovery.
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http://dx.doi.org/10.1039/c8cp07002dDOI Listing
February 2019

Identifying New AMP-Activated Protein Kinase Inhibitors That Protect against Ischemic Brain Injury.

ACS Chem Neurosci 2019 05 22;10(5):2345-2354. Epub 2019 Feb 22.

Department of Molecular Biology , Sejong University , Seoul 05006 , Republic of Korea.

We recently reported that AMP-activated protein kinase (AMPK) contributes to zinc-induced neuronal death by inducing Bim, a pro-apoptotic Bcl-2 homology domain 3-only protein, in a liver kinase B1 (LKB1)-dependent manner. Current data suggest AMPK plays key roles in excitotoxicity and ischemic brain injury, with zinc neurotoxicity representing at least one mechanism of ischemic neuronal death. Inhibition of AMPK could be a viable therapeutic strategy to prevent ischemic brain injury following stroke. This prompted our search for novel inhibitors of AMPK activity and zinc-induced neuronal death using cultured mouse cortex and a rat model of brain injury after middle cerebral artery occlusion (MCAO). In structure-based virtual screening, 118 compounds were predicted to bind the active site of AMPK α2, and 40 showed in vitro AMPK α2 inhibitory activity comparable to compound C (a well-known, potent AMPK inhibitor). In mouse cortical neuronal cultures, 7 of 40 compound reduced zinc-induced neuronal death at levels comparable to compound C. Ultimately, only agents 2G11 and 1H10 significantly attenuated various types of neuronal death, including oxidative stress, excitotoxicity, and apoptosis. When administered as intracerebroventricular injections prior to permanent MCAO in rats, 2G11 and 1H10 reduced brain infarct volumes, whereas compound C did not. Therefore, these novel AMPK inhibitors could be drug development candidates to treat stroke.
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http://dx.doi.org/10.1021/acschemneuro.8b00654DOI Listing
May 2019

Identification of N-(5-(phenoxymethyl)-1,3,4-thiadiazol-2-yl)acetamide derivatives as novel protein tyrosine phosphatase epsilon inhibitors exhibiting anti-osteoclastic activity.

Bioorg Med Chem 2018 10 19;26(18):5204-5211. Epub 2018 Sep 19.

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Bioscience, University of Science and Technology KRIBB School, Daejeon 34113, Republic of Korea. Electronic address:

Cytosolic protein tyrosine phosphatase epsilon (cyt-PTPε) plays a central role in controlling differentiation and function of osteoclasts, whose overactivation causes osteoporosis. Based on our previous study reporting a number of cyt-PTPε inhibitory chemical compounds, we carried out a further and extended analysis of our compounds to examine their effects on cyt-PTPε-mediated dephosphorylation and on osteoclast organization and differentiation. Among five compounds showing target selectivity to cyt-PTPε over three other phosphatases in vitro, two compounds exhibited an inhibitory effect against the dephosphorylation of cellular Src protein, the cyt-PTPε substrate. Moreover, these two compounds caused destabilization of the podosome structure that is necessary for the bone-resorbing activity of osteoclasts, and also attenuated cellular differentiation of monocytes into osteoclasts, without affecting cell viability. Therefore, these findings not only verified anti-osteoclastic effects of our cyt-PTPε inhibitory compounds, but also showed that cyt-PTPε expressed in osteoclasts could be a putative therapeutic target worth considering.
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http://dx.doi.org/10.1016/j.bmc.2018.09.022DOI Listing
October 2018

Rapid and simple detection of Tamiflu-resistant influenza virus: Development of oseltamivir derivative-based lateral flow biosensor for point-of-care (POC) diagnostics.

Sci Rep 2018 08 29;8(1):12999. Epub 2018 Aug 29.

Hazards Monitoring BioNano Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, Korea.

We have developed a novel oseltamivir derivative (oseltamivir hexylthiol; OHT) that exhibits a higher binding affinity for Tamiflu-resistant virus (Tamiflu resistance) than for the wild-type virus (Tamiflu-susceptible virus; WT) as an antibody. First, OHT-modified gold nanoparticles (OHT-GNPs) are used in a simple colorimetric assay as nanoprobes for the Tamiflu-resistant virus. In the presence of Tamiflu-resistant virus, they show a colorimetric change from deep red to purple because of the OHT-GNP aggregation driven by strong interactions between OHT and neuraminidase (NA) on the surface of the Tamiflu-resistance. Moreover, the color gradually turns purple as the concentration of the Tamiflu-resistant virus increases, allowing the determination of the presence of the virus with the naked eye. Furthermore, an OHT-based lateral flow assay (LFA) has been developed as a rapid and easy detection device for Tamiflu resistance. It shows detection specificity for various virus concentrations of Tamiflu-resistant virus even for the mixture of WT and Tamiflu-resistant viruses, where the limit of detection (LOD) is 5 × 10 ~ 10 PFU per test (=1 × 10 PFU/mL). It has been confirmed that this platform can provide accurate information on whether a virus exhibits Tamiflu resistance, thus supporting the selection of appropriate treatments using point-of-care (POC) diagnostics.
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http://dx.doi.org/10.1038/s41598-018-31311-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115449PMC
August 2018

Systematic Computational Design and Identification of Low Picomolar Inhibitors of Aurora Kinase A.

J Chem Inf Model 2018 03 16;58(3):700-709. Epub 2018 Feb 16.

Center for Catalytic Hydrocarbon Functionalizations , Institute for Basic Science (IBS) , Daejeon 34141 , Korea.

Aurora kinase A (AKA) has served as an effective molecular target for the development of cancer therapeutics. A series of potent AKA inhibitors with the (4-methoxy-pyrimidin-2-yl)-phenyl-amine (MPPA) scaffold are identified using a systematic computer-aided drug design protocol involving structure-based virtual screening, de novo design, and free energy perturbation (FEP) simulations. To enhance the accuracy of the virtual screening to find a proper molecular core and de novo design to optimize biochemical potency, we preliminarily improved the scoring function by implementing a reliable hydration energy term. The overall design strategy proves successful to the extent that some inhibitors reveal exceptionally high potency at low picomolar levels; this was achieved by substituting phenyl, chlorine, and tetrazole moieties on the MPPA scaffold. The establishment of bidentate hydrogen bonds with backbone groups in the hinge region appears to be necessary for the high biochemical potency, consistent with the literature X-ray crystallographic data. The picomolar inhibitory activity also stems from the simultaneous formation of additional hydrogen bonds with the side chains of the hinge region and P-loop residues. The FEP simulation results show that the inhibitory activity surges to the low picomolar level because the interactions in the ATP-binding site of AKA become strong by structural modifications enough to overbalance the increase in dehydration cost. Because of the exceptionally high biochemical potency, the AKA inhibitors reported in this study are anticipated to serve as a new starting point for the discovery of anticancer medicine.
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http://dx.doi.org/10.1021/acs.jcim.7b00671DOI Listing
March 2018

Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1.

J Comput Aided Mol Des 2017 Aug 26;31(8):743-753. Epub 2017 Jun 26.

Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea.

Despite a wealth of persuasive evidence for the involvement of human small C-terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington's disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations.
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http://dx.doi.org/10.1007/s10822-017-0037-2DOI Listing
August 2017

Discovery of EGF Receptor Inhibitors That Are Selective for the d746-750/T790M/C797S Mutant through Structure-Based de Novo Design.

Angew Chem Int Ed Engl 2017 06 22;56(26):7634-7638. Epub 2017 May 22.

Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Korea.

Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.
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http://dx.doi.org/10.1002/anie.201703389DOI Listing
June 2017

Anticancer activity of a novel small molecule tubulin inhibitor STK899704.

PLoS One 2017 15;12(3):e0173311. Epub 2017 Mar 15.

Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Cheongwon, Korea.

We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines. The proposed binding mode of STK899704 is at the interface between αβ-tubulin heterodimer overlapping with the colchicine-binding site. Our in vivo carcinogenesis model further showed that STK 899704 is potent in both the prevention and regression of tumors, remarkably reducing the number and volume of skin tumor by STK899704 treatment. Moreover, it was significant to note that the efficacy of STK899704 was surprisingly comparable to 5-fluorouracil, a widely used anticancer therapeutic. Thus, our results demonstrate the potential of STK899704 to be developed as an anticancer chemotherapeutic and an alternative candidate for existing therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173311PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351965PMC
September 2017

NPCARE: database of natural products and fractional extracts for cancer regulation.

J Cheminform 2017 5;9. Epub 2017 Jan 5.

Department of Bioscience and Biotechnology, Institute of Anticancer Medicine Development, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul, 05006 Korea.

Background: Natural products have increasingly attracted much attention as a valuable resource for the development of anticancer medicines due to the structural novelty and good bioavailability. This necessitates a comprehensive database for the natural products and the fractional extracts whose anticancer activities have been verified.

Description: NPCARE (http://silver.sejong.ac.kr/npcare) is a publicly accessible online database of natural products and fractional extracts for cancer regulation. At NPCARE, one can explore 6578 natural compounds and 2566 fractional extracts isolated from 1952 distinct biological species including plants, marine organisms, fungi, and bacteria whose anticancer activities were validated with 1107 cell lines for 34 cancer types. Each entry in NPCARE is annotated with the cancer type, genus and species names of the biological resource, the cell line used for demonstrating the anticancer activity, PubChem ID, and a wealth of information about the target gene or protein. Besides the augmentation of plant entries up to 743 genus and 197 families, NPCARE is further enriched with the natural products and the fractional extracts of diverse non-traditional biological resources.

Conclusions: NPCARE is anticipated to serve as a dominant gateway for the discovery of new anticancer medicines due to the inclusion of a large number of the fractional extracts as well as the natural compounds isolated from a variety of biological resources.
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http://dx.doi.org/10.1186/s13321-016-0188-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267755PMC
January 2017

The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice.

Toxicol Appl Pharmacol 2017 Jan 8;315:80-89. Epub 2016 Dec 8.

Department of Ophthalmology, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC.
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http://dx.doi.org/10.1016/j.taap.2016.12.004DOI Listing
January 2017

Molecular Characterization of Two Monoclonal Antibodies against the Same Epitope on B-Cell Receptor Associated Protein 31.

PLoS One 2016 1;11(12):e0167527. Epub 2016 Dec 1.

Institute of Anticancer Medicine Development, Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, Korea.

Previously, we showed that B-cell receptor associated protein 31 (BAP31), an endoplasmic reticulum (ER) membrane chaperone, is also expressed on the cell surface by two monoclonal antibodies (MAbs) 297-D4 and 144-A8. Both MAbs recognize the same linear epitope on the C-terminal domain of BAP31, although they were independently established. Here, flow cytometric analysis showed that 144-A8 had additional binding properties to some cells, as compared to 297-D4. Quantitative antigen binding assays also showed that 144-A8 had higher antigen binding capacity than 297-D4. Affinity measurement revealed that 144-A8 had 1.54-fold higher binding affinity than 297-D4. Analysis of the heavy- and light-chain variable region sequences of two MAbs revealed that both MAbs belonged to the same heavy chain (Igh-V3660 VH3) and light chain subgroup (IGKV21) with just two amino acid differences in each framework region, indicating that both MAbs arise from the same germline origin. Seven amino acid differences were found between the complementarity determining regions (CDRs) of the two MAbs. Molecular modeling of the epitope-paratope complexes revealed that the epitope appeared to reside in closer proximity to the CDRs of 144-A8 than to those of 297-D4 with the stronger hydrogen bond interactions with the former than the latter. More interestingly, an additional hydrophobic interaction appeared to be established between the leucine residue of epitope and the paratope of 144-A8, due to the substitution of H-Tyr101 for H-Phe101 in 144-A8. Thus, the different binding specificity and affinity of 144-A8 appeared to be due to the different hydrogen bonds and hydrophobic interaction induced by the alterations of amino acids in CDRs of 144-A8. The results provide molecular insights into how the binding specificities and affinities of antibodies evolve with the same epitope in different microenvironments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167527PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131989PMC
June 2017

Application of Fragment-Based de Novo Design to the Discovery of Selective Picomolar Inhibitors of Glycogen Synthase Kinase-3 Beta.

J Med Chem 2016 10 30;59(19):9018-9034. Epub 2016 Sep 30.

Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Yuseong-gu, E6-4, Daejeon 305-701, Korea.

A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3β). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3β through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent-contact model, we identified several GSK3β inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (12 and 27) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3β because of the high specificity for the inhibition of GSK3β.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00944DOI Listing
October 2016

Extended solvent-contact model approach to blind SAMPL5 prediction challenge for the distribution coefficients of drug-like molecules.

J Comput Aided Mol Des 2016 11 23;30(11):1019-1033. Epub 2016 Jul 23.

Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul, 143-747, Republic of Korea.

The performance of the extended solvent-contact model has been addressed in the SAMPL5 blind prediction challenge for distribution coefficient (LogD) of drug-like molecules with respect to the cyclohexane/water partitioning system. All the atomic parameters defined for 41 atom types in the solvation free energy function were optimized by operating a standard genetic algorithm with respect to water and cyclohexane solvents. In the parameterizations for cyclohexane, the experimental solvation free energy (ΔG ) data of 15 molecules for 1-octanol were combined with those of 77 molecules for cyclohexane to construct a training set because ΔG values of the former were unavailable for cyclohexane in publicly accessible databases. Using this hybrid training set, we established the LogD prediction model with the correlation coefficient (R), average error (AE), and root mean square error (RMSE) of 0.55, 1.53, and 3.03, respectively, for the comparison of experimental and computational results for 53 SAMPL5 molecules. The modest accuracy in LogD prediction could be attributed to the incomplete optimization of atomic solvation parameters for cyclohexane. With respect to 31 SAMPL5 molecules containing the atom types for which experimental reference data for ΔG were available for both water and cyclohexane, the accuracy in LogD prediction increased remarkably with the R, AE, and RMSE values of 0.82, 0.89, and 1.60, respectively. This significant enhancement in performance stemmed from the better optimization of atomic solvation parameters by limiting the element of training set to the molecules with experimental ΔG data for cyclohexane. Due to the simplicity in model building and to low computational cost for parameterizations, the extended solvent-contact model is anticipated to serve as a valuable computational tool for LogD prediction upon the enrichment of experimental ΔG data for organic solvents.
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http://dx.doi.org/10.1007/s10822-016-9928-xDOI Listing
November 2016

Investigations on recyclisation and hydrolysis in avibactam mediated serine β-lactamase inhibition.

Org Biomol Chem 2016 Apr;14(17):4116-28

Chemical Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.

β-Lactams inhibit penicillin-binding proteins (PBPs) and serine β-lactamases by acylation of a nucleophilic active site serine. Avibactam is approved for clinical use in combination with ceftazidime, and is a breakthrough non β-lactam β-lactamase inhibitor also reacting via serine acylation. Molecular dynamics (MD) and quantum chemical calculations on avibactam-mediated inhibition of a clinically relevant cephalosporinase reveal that recyclisation of the avibactam derived carbamoyl complex is favoured over hydrolysis. In contrast, we show that analogous recyclisation in β-lactam mediated inhibition is disfavoured. Avibactam recyclisation is promoted by a proton shuttle, a 'structural' water protonating the nucleophilic serine, and stabilization of the negative charge developed on aminocarbonyl oxygen. The results imply the potential of calculations for distinguishing between bifurcating pathways during inhibition and in generating hypotheses for predicting resistance. The inability of β-lactams to undergo recyclisation may be an Achilles heel, but one that can be addressed by suitably functionalized reversibly binding inhibitors.
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http://dx.doi.org/10.1039/c6ob00353bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847122PMC
April 2016

Discovery of Low Micromolar Dual Inhibitors for Wild Type and L1196M Mutant of Anaplastic Lymphoma Kinase through Structure-Based Virtual Screening.

J Chem Inf Model 2016 04 4;56(4):802-10. Epub 2016 Apr 4.

Department of Bioscience and Biotechnology & Institute of Anticancer Medicine Development, Sejong University , 209 Neungdong-ro, Kwangjin-gu, Seoul 143-747, Korea.

Although anaplastic lymphoma kinase (ALK) is involved in a variety of malignant human cancers, the emergence of constitutively active mutants with drug resistance has rendered it difficult to identify the new medicines for ALK-dependent cancers. To find the common inhibitors of the wild type ALK and the most abundant drug-resistant mutant (L1196M), we performed molecular docking-based virtual screening of a large chemical library in parallel for the two target proteins. As a consequence of augmenting the accuracy of the docking simulation by implementing a sophisticated hydration free energy term in the scoring function, 12 common inhibitors are discovered with the inhibitory activities ranging from submicromolar to low micromolar levels. The results of the binding free energy decomposition indicate that the biochemical potency of ALK inhibitors can be optimized by reducing the dehydration cost for binding to the receptor protein as well as by strengthening the interactions with amino acid residues in the ATP-binding site. The newly identified ALK inhibitors are found to have a little higher inhibitory activity for the L1196M mutant than for the wild type due to the strengthening of the hydrogen bond interactions in the ATP-binding site. Of the 12 common inhibitors, 2-(5-methyl-benzooxazol-2-ylamino)-quinazolin-4-ol (3) is anticipated to serve as a new molecular scaffold to optimize the biochemical potency because it exhibits low micromolar inhibitory activity with respect to both the wild type and L1196M mutant in spite of the low molecular weight (292.3 amu).
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http://dx.doi.org/10.1021/acs.jcim.6b00026DOI Listing
April 2016

Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition.

Sci Rep 2016 Feb 23;6:21772. Epub 2016 Feb 23.

Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.

Resveratrol (RSV) is a natural polyphenol that has a beneficial effect on health, and resveratrol-induced autophagy has been suggested to be a key process in mediating many beneficial effects of resveratrol, such as reduction of inflammation and induction of cancer cell death. Although various resveratrol targets have been suggested, the molecule that mediates resveratrol-induced autophagy remains unknown. Here, we demonstrate that resveratrol induces autophagy by directly inhibiting the mTOR-ULK1 pathway. We found that inhibition of mTOR activity and presence of ULK1 are required for autophagy induction by resveratrol. In line with this mTOR dependency, we found that resveratrol suppresses the viability of MCF7 cells but not of SW620 cells, which are mTOR inhibitor sensitive and insensitive cancer cells, respectively. We also found that resveratrol-induced cancer cell suppression occurred ULK1 dependently. For the mechanism of action of resveratrol on mTOR inhibition, we demonstrate that resveratrol directly inhibits mTOR. We found that resveratrol inhibits mTOR by docking onto the ATP-binding pocket of mTOR (i.e., it competes with ATP). We propose mTOR as a novel direct target of resveratrol, and inhibition of mTOR is necessary for autophagy induction.
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http://dx.doi.org/10.1038/srep21772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763238PMC
February 2016

The Composite Structure and Two-Peak Emission Behavior of a Ca1.5Ba0.5Si5O3N6:Eu(2+) Phosphor.

Inorg Chem 2016 Mar 22;55(5):2534-43. Epub 2016 Feb 22.

LED Division, Samsung Electronics , Suwon, Kyunggi 443-742, Korea.

A Ca1.5Ba0.5Si5O3N6:Eu(2+) 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:Eu(2+) phosphor could be suitable for light-emitting diode applications since it exhibited a promising yellow (or amber) emission peaking at ∼ 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 and time-resolved photoluminescence. In addition, the energy transfer between two activator sites ascribed to the composite structure was examined in detail.
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http://dx.doi.org/10.1021/acs.inorgchem.5b02884DOI Listing
March 2016

Discovery of Dual Inhibitors for Wild Type and D816V Mutant of c-KIT Kinase through Virtual and Biochemical Screening of Natural Products.

J Nat Prod 2016 Feb 25;79(2):293-9. Epub 2016 Jan 25.

Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS) & Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 305-701, Korea.

Although stem cell factor receptor (c-KIT) kinase is responsible for various malignant human cancers, the presence of constitutively active gain-of-function mutants has made it difficult to discover new anticancer agents using c-KIT as the target protein. To identify the common inhibitors of wild-type c-KIT and the most abundant gain-of-function mutant (D816V), the virtual screening of natural products was performed for the two target proteins in parallel with the scoring function improved by implementing a sophisticated solvation free energy term. As a result, four common inhibitors of natural origin are found with biochemical potencies ranging from low micromolar to submicromolar levels. The results of extensive docking simulations show that although the natural-product inhibitors establish weaker hydrophobic interactions with the D816V mutant than with the wild type, they exhibit a little higher inhibitory activity for the former than the latter by strengthening the hydrogen-bond interactions to a sufficient extent. Of the four natural-product inhibitors, (Z)-6-hydroxy-2-(4-methoxybenzylidene)benzofuran-3(2H)-one (3) is anticipated to serve as a new molecular core for the structure-activity relationship studies to optimize the biochemical potencies because it exhibits good inhibitory activity against both the wild type and D816V mutant despite its low molecular weight (268.3 amu).
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http://dx.doi.org/10.1021/acs.jnatprod.5b00851DOI Listing
February 2016

Accuracy enhancement in the estimation of molecular hydration free energies by implementing the intramolecular hydrogen bond effects.

J Cheminform 2015 25;7:57. Epub 2015 Nov 25.

Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul, 143-747 Republic of Korea.

Background: The formation of intramolecular hydrogen bonds (IHBs) may induce the remarkable changes in molecular physicochemical properties. Within the framework of the extended solvent-contact model, we investigate the effect of implementing the IHB interactions on the accuracy in estimating the molecular hydration free energies.

Results: The performances of hydration free energy functions including and excluding the IHB parameters are compared using the molecules distributed for SAMPL4 blind prediction challenge and those in Free Solvation Database (FSD). The calculated hydration free energies with IHB effects are found to be in considerably better agreement with the experimental data than those without them. For example, the root mean square error of the estimation decreases from 2.56 to 1.66 and from 1.73 to 1.54 kcal/mol for SAMPL4 and FSD molecules, respectively, due to the extension of atomic parameter space to cope with IHBs.

Conclusions: These improvements are made possible by reducing the overestimation of attractive interactions between water and the solute molecules involving IHBs. The modified hydration free energy function is thus anticipated to be useful for estimating the desolvation cost for various organic molecules.
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http://dx.doi.org/10.1186/s13321-015-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660792PMC
November 2015

Identification of novel protein tyrosine phosphatase sigma inhibitors promoting neurite extension.

Bioorg Med Chem Lett 2016 Jan 10;26(1):87-93. Epub 2015 Nov 10.

Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea. Electronic address:

Protein tyrosine phosphatase sigma (PTPσ) is a potential target for the therapeutic treatment of neurological deficits associated with impaired neuronal recovery, as this protein is the receptor for chondroitin sulfate proteoglycan (CSPG), which is known to inhibit neuronal regeneration. Through a high-throughput screening approach started from 6400 representative compounds in the Korea Chemical Bank chemical library, we identified 11 novel PTPσ inhibitors that can be classified as flavonoid derivatives or analogs, with IC50 values ranging from 0.5 to 17.5μM. Biochemical assays and structure-based active site-docking simulation indicate that our inhibitors are accommodated at the catalytic active site of PTPσ as surrogates for the phosphotyrosine group. Treatments of these compounds on PC-12 neuronal cells led to the recovery of neurite extension attenuated by CSPG treatment, demonstrating their potential as antineurodegenerative agents.
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http://dx.doi.org/10.1016/j.bmcl.2015.11.026DOI Listing
January 2016

Computational prediction of molecular hydration entropy with hybrid scaled particle theory and free-energy perturbation method.

J Chem Theory Comput 2015 Oct 30;11(10):4933-42. Epub 2015 Sep 30.

Department of Bioscience and Biotechnology, Sejong University , 209 Neungdong-ro, Kwangjin-gu, Seoul 143-747, Korea.

Despite the importance of the knowledge of molecular hydration entropy (ΔShyd) in chemical and biological processes, the exact calculation of ΔShyd is very difficult, because of the complexity in solute-water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating ΔShyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute-water interaction term (ΔSelec) and the hydrophobic contribution approximated by the cavity formation entropy (ΔScav), respectively. Decomposition of ΔShyd into ΔScav and ΔSelec terms is found to be very effective with a substantial accuracy enhancement in ΔShyd estimation, when compared to the conventional full FEP calculations. ΔScav appears to dominate over ΔSelec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of ΔShyd prediction by effectively complementing the conventional full FEP method.
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http://dx.doi.org/10.1021/acs.jctc.5b00325DOI Listing
October 2015

Virtual Screening with Docking Simulations and Biochemical Evaluation of VHY Phosphatase Inhibitors.

Chem Pharm Bull (Tokyo) 2015 ;63(10):807-11

Department of Bioscience and Biotechnology, Sejong University.

Although VH1-related member Y (VHY) phosphatase is responsible for the pathogenesis of neuroinflammatory diseases, no small-molecule inhibitor of VHY has been reported so far. Here we first report eight VHY inhibitors identified from molecular docking-based virtual screening and subsequent enzyme inhibition assays. These inhibitors exhibit good biochemical potencies against VHY, with associated IC50 values ranging from 1 to 9 µM. Because all these inhibitors were also screened in silico for having desirable physicochemical properties as a drug candidate, they deserve further investigation by structure-activity relationship studies to develop new medicines for the treatment of neuroinflammatory diseases. The structural features of VHY-inhibitor interactions relevant to the micromolar-level inhibitory activity are addressed in detail.
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http://dx.doi.org/10.1248/cpb.c15-00431DOI Listing
July 2016

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

Bioorg Med Chem Lett 2015 Sep 5;25(18):3784-7. Epub 2015 Aug 5.

Center for Catalytic Hydrocarbon Functionalization, Institute for Basic Science (IBS) & Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address:

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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http://dx.doi.org/10.1016/j.bmcl.2015.07.094DOI Listing
September 2015

Computational prediction of octanol-water partition coefficient based on the extended solvent-contact model.

J Mol Graph Model 2015 Jul 16;60:108-17. Epub 2015 Jun 16.

Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 143-747, Republic of Korea. Electronic address:

The logarithm of 1-octanol/water partition coefficient (LogP) is one of the most important molecular design parameters in drug discovery. Assuming that LogP can be calculated from the difference between the solvation free energy of a molecule in water and that in 1-octanol, we propose a method for predicting the molecular LogP values based on the extended solvent-contact model. To obtain the molecular solvation free energy data for the two solvents, a proper potential energy function was defined for each solvent with respect to atomic distributions and three kinds of atomic parameters. Total 205 atomic parameters were optimized with the standard genetic algorithm using the training set consisting of 139 organic molecules with varying shapes and functional groups. The LogP values estimated with the two optimized solvation free energy functions compared reasonably well with the experimental results with the associated squared correlation coefficient and root mean square error of 0.824 and 0.697, respectively. Besides the prediction accuracy, the present method has the merit in practical applications because molecular LogP values can be computed straightforwardly from the simple potential energy functions without the need to calculate various molecular descriptors. The methods for enhancing the accuracy of the present prediction model are also discussed.
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http://dx.doi.org/10.1016/j.jmgm.2015.06.004DOI Listing
July 2015