Jin Huang

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Name: 黄瑾; Huang, Jin

Organization: East China University of Science and Technology , China

Department: School of Pharmacy

Title: Professor(PhD)

Chemicals
References

Discovery of new antimalarial agents: Second-generation dual inhibitors against FP-2 and PfDHFR via fragments assembely

Co-reporter:Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu

Bioorganic & Medicinal Chemistry 2017 Volume 25, Issue 24(Issue 24) pp:

Publication Date(Web):15 December 2017

DOI:10.1016/j.bmc.2017.10.017

Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50 = 10.0 µM), PfDHFR (IC50 = 84.1 nM), P. falciparum 3D7 (IC50 = 53.1 nM), clinical isolated strains Fab9 (IC50 = 14.2 nM) and GB4 (IC50 = 23.4 nM). The in vivo inhibition assays against P. berghei in 10 days indicated 24 had a more beneficial effect on the growth inhibition of P. berghei than artemisinin and an identical effect with pyrimethamine. Additionally, 24 moderately inhibited the proliferation of chloroquine-resistant P. falciparum Dd2 strain. Collectively, these data revealed that 24 could be an excellent lead compound as FP-2 and PfDHFR dual inhibitor for the treatment of malaria.Download high-res image (83KB)Download full-size image

Synthesis and biological evaluation of novel 1,2,3-benzotriazin-4-one derivatives as leukotriene A4 hydrolase aminopeptidase inhibitors

Co-reporter:Fan Zhang, Dang Wu, Gao-Lei Wang, Shuang Hou, ... Xiao-Yong Xu

Chinese Chemical Letters 2017 Volume 28, Issue 5(Volume 28, Issue 5) pp:

Publication Date(Web):1 May 2017

DOI:10.1016/j.cclet.2016.12.014

A series of novel 1,2,3-benzotriazin-4-one derivatives were designed, synthesized and their inhibitory activities against leukotriene A4 hydrolase aminopeptidase in vitro were evaluated. Many compounds showed moderate to good activities at the concentration of 10 μmol/L. Among them, compound IV-16 exhibited the highest inhibitory activity up to 80.6% with an IC50 of 1.30 ± 0.20 μmol/L. The compound IV-16 was also tested the proliferation inhibitory activities in THP1 human AML cell line and its binding model with LTA4H enzyme by molecular docking was studied. It indicated that 1,2,3-benzotriazin-4-one was a promising scaffold for further study. The relationship between structure and inhibitory activity was also preliminarily discussed.Download high-res image (92KB)Download full-size imageNovel 1,2,3-triazin-4-one derivatives incorporating 4-thiazolidinone moieties were designed and synthesized. Many of them exhibited moderate to good inhibitory activity against LTA4H aminopeptidase at 10 μmol/L, the compound IV-16 with best bioactivity was also tested the proliferation inhibitory activities in THP1 human AML cell line and its binding model with LTA4H enzyme by molecular docking was studied. It indicated that 1,2,3-triazin-4-one was a very promising scaffold to study further.

New tricks for human farnesyltransferase inhibitor: cancer and beyond

Co-reporter:Jingyuan Wang;Xue Yao

MedChemComm (2010-Present) 2017 vol. 8(Issue 5) pp:841-854

Publication Date(Web):2017/05/24

DOI:10.1039/C7MD00030H

Human protein farnesyltransferase (FTase) catalyzes the addition of a C15-farnesyl lipid group to the cysteine residue located in the COOH-terminal tetrapeptide motif of a variety of important substrate proteins, including well-known Ras protein superfamily. The farnesylation of Ras protein is required both for its normal physiological function, and for the transforming capacity of its oncogenic mutants. Over the last several decades, FTase inhibitors (FTIs) were developed to disrupt the farnesylation of oncogenic Ras as anti-cancer agents, and some of them have entered cancer clinical investigation. On the other hand, some substrates of FTase were demonstrated to be related with other human diseases, including Hutchinson–Gilford progeria syndrome, chronic hepatitis D, and cardiovascular diseases. In this review, we summarize the roles of FTase in malignant transformation, proliferation, apoptosis, angiogenesis, and metastasis of tumor cells, and the recently anticancer clinical research advances of FTIs. The therapeutic prospect of FTIs on several other human diseases is also discussed.

Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis

Co-reporter:Weiqiang Lu, Xue Yao, Ping Ouyang, Ningning Dong, Dang Wu, Xingwu Jiang, Zengrui Wu, Chen Zhang, Zhongyu Xu, Yun TangShien Zou, Mingyao Liu, Jian Li, Minghua ZengPing Lin, Feixiong Cheng, Jin Huang

Journal of Medicinal Chemistry 2017 Volume 60(Issue 5) pp:

Publication Date(Web):February 20, 2017

DOI:10.1021/acs.jmedchem.6b01507

Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.

Isoindole-1,3-dione derivatives as RSK2 inhibitors: synthesis, molecular docking simulation and SAR analysis

Co-reporter:Wei Zhou, Shiliang Li, Weiqiang Lu, Jun Yuan, Yufang Xu, Honglin Li, Jin Huang and Zhenjiang Zhao

MedChemComm 2016 vol. 7(Issue 2) pp:292-296

Publication Date(Web):25 Nov 2015

DOI:10.1039/C5MD00469A

RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our previous study. Some compounds were confirmed to be moderately potent RSK2 inhibitors with IC50 values of about 0.5 μM. Structure–activity relationship analysis and binding mode studies by molecular docking were performed.

Detection of mammalian 5-lipoxygenase activity using the fluorescent probe dihydrorhodamine 123

Co-reporter:Xue Zhao;Weiqiang Lu;Cheng Song

European Journal of Lipid Science and Technology 2014 Volume 116( Issue 2) pp:119-125

Publication Date(Web):

DOI:10.1002/ejlt.201300104

In this article, we describe a new, fast and reliable method for determining 5-LOX activity using the fluorescent probe dihydrorhodamine 123 (DHR). In the new assay, the products of 5-LOX, 5S-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, can directly oxidize non-fluorescent DHR to highly fluorescent rhodamine 123. The fluorescence intensity can be measured using fluorescence spectroscopy at Ex/Em = 500/536 nm. As 5-LOX requires some cofactors to achieve its optimum activity, the effects of its cofactors on the fluorescence assay are also investigated. Using this new assay, we evaluated the inhibitory activity of two well-known 5-LOX inhibitors (NDGA and AA861) in a 384-well format and the IC₅₀ values of them are consistent with previously references. The fluorescence assay is amenable to both purified 5-LOX and 5-LOX in cell lysates and will be widely used for the discovery of novel 5-LOX inhibitors for clinical application.

Identification of diverse natural products as falcipain-2 inhibitors through structure-based virtual screening

Co-reporter:Liyan Wang, Shoude Zhang, Junsheng Zhu, Lili Zhu, Xiaofeng Liu, Lei Shan, Jin Huang, Weidong Zhang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 5) pp:1261-1264

Publication Date(Web):1 March 2014

DOI:10.1016/j.bmcl.2014.01.074

Ten natural compounds are successfully identified as falcipain-2 (FP-2) inhibitors from our in-house natural products database using structure-based virtual screening, which show moderate inhibitory activities against FP-2 with IC50 values ranging from 3.18 to 68.19 μM. While one of the inhibitors (compound 5) also exhibits in vitro antiplasmodial activity against chloroquine sensitive strain (3D7) and chloroquine resistant strain (Dd2) of Plasmodium falciparum in the micromolar range (IC50s = 5.54 μM and 4.05 μM against 3D7 cells and Dd2 cells, respectively). Furthermore, the predicted binding poses are analyzed to explain the structure–activity relationships, which will be helpful for further structural modifications.

Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1)

Co-reporter:Hu Yuan, Weiqiang Lu, Liyan Wang, Lei Shan, Honglin Li, Jin Huang, Qingyan Sun, Weidong Zhang

European Journal of Medicinal Chemistry 2013 Volume 62() pp:148-157

Publication Date(Web):April 2013

DOI:10.1016/j.ejmech.2012.09.047

A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM. A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with MMP-1. The structure–activity relationships (SAR) were also briefly discussed. Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against MMP-1.Graphical abstractSeveral MMP-1 inhibitors have been identified using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM.Highlights► A series of methyl rosmarinate analogs were synthesized. ► The compounds were tested for their inhibitory activities against MMP-1. ► The structure–activity relationships of compounds have been discussed.

Discovery of new potent inhibitors for carbonic anhydrase IX by structure-based virtual screening

Co-reporter:Liyan Wang, Chunmei Yang, Weiqiang Lu, Li Liu, Rui Gao, Sha Liao, Zhenjiang Zhao, Lili Zhu, Yufang Xu, Honglin Li, Jin Huang, Weiping Zhu

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 12) pp:3496-3499

Publication Date(Web):15 June 2013

DOI:10.1016/j.bmcl.2013.04.048

Through structure-based virtual screening, some dozen of benzene sulfonamides with novel scaffolds are identified as potent inhibitors against carbonic anhydrase (CA) IX with IC50 values ranging from 2.86 to 588.34 nM. Among them, compounds 1 and 9 show high selectivity against tumor-target CA IX over CA II (the selectivity ratios are 21.3 and 136.6, respectively). The possible binding poses of hit compounds are also explored and the selectivity is elucidated by molecular docking simulations. The hit compounds discovered in this work would provide novel scaffolds for further hit-to-lead optimization.

Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening

Co-reporter:Yuwei Song, Huangtao Jin, Xiaofeng Liu, Lili Zhu, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 7) pp:2078-2082

Publication Date(Web):1 April 2013

DOI:10.1016/j.bmcl.2013.01.128

Plasmepsin II (PM II) is an attractive target for anti-malaria drug discovery, which involves in host hemoglobin degradation in the acidic food vacuole. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PM II from two chemical database. Five novel non-peptide inhibitors were identified and revealed moderate inhibitory potencies with IC50 ranged from 4.62 ± 0.39 to 9.47 ± 0.71 μM. The detailed analysis of binding modes using docking simulations for five inhibitors showed that the inhibitors could be stabilized by forming multiple hydrogen bonds with catalytic residues (Asp 34 and Asp 214) and also with other key residues.

Discovery of natural estrogen receptor modulators with structure-based virtual screening

Co-reporter:Xianwen Cao, Jing Jiang, Shoude Zhang, Lili Zhu, Juan Zou, Yanyan Diao, Weilie Xiao, Lei Shan, Handong Sun, Weidong Zhang, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 11) pp:3329-3333

Publication Date(Web):1 June 2013

DOI:10.1016/j.bmcl.2013.03.105

Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68 μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation.

Discovery of novel inhibitors for human farnesyltransferase (hFTase) via structure-based virtual screening

Co-reporter:Xiaojuan Yu, Xue Zhao, Lili Zhu, Chuanxin Zou, Xiaofeng Liu, Zhenjiang Zhao, Jin Huang and Honglin Li

MedChemComm 2013 vol. 4(Issue 6) pp:962-971

Publication Date(Web):10 Apr 2013

DOI:10.1039/C3MD00058C

In this study, 22 novel hFTase inhibitors containing 18 scaffolds were identified with IC50 values ranging from 0.0119 to 13.35 μM by structure-based virtual screening, and compounds 2, 7, 9, 10, 14 and 15 showed moderate antiproliferative activity against MCF-7 cells. In particular, compound 2 was the most promising lead compound with nanomolar activity against FTase and antiproliferative activity in the low micromolar range. Possible binding modes of the hit compounds were explored and their structure–activity relationships (SAR) were elucidated by molecular docking simulation. The hit compounds discovered in this work will provide novel scaffolds for further hit-to-lead optimization and lay the foundation for further development of therapeutic candidates for cancer treatments.

Development of a new colorimetric assay for lipoxygenase activity

Co-reporter:Weiqiang Lu, Xue Zhao, Zhongyu Xu, Ningning Dong, Shien Zou, Xu Shen, Jin Huang

Analytical Biochemistry 2013 Volume 441(Issue 2) pp:162-168

Publication Date(Web):15 October 2013

DOI:10.1016/j.ab.2013.06.007

Abstract

Lipoxygenases (LOXs) are a family of non-heme iron-containing dioxygenases that catalyze the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. A rapid and reliable colorimetric assay for determination of the activity of three human functional lipoxygenase isoforms (5-lipoxygenase, platelet 12-lipoxygenase, and 15-lipoxygenase-1) is developed in this article. In the new assay, LOX-derived lipid hydroperoxides oxidize the ferrous ion (Fe²⁺) to the ferric ion (Fe³⁺), the latter of which binds with thiocyanate (SCN^–) to generate a red ferrithiocyanate (FTC) complex. The absorbance of the FTC complex can be easily measured at 480 nm. Because 5-LOX can be stimulated by many cofactors, the effects of its cofactors (Ca²⁺, ATP, dithiothreitol, glutathione, l-α-phosphatidylcholine, and ethylenediaminetetraacetic acid) on the color development of the FTC complex are also determined. The assay is adaptive for purified LOXs and cell lysates containing active LOXs. We use the new colorimetric assay in a 96-well format to evaluate several well-known LOX inhibitors, the IC₅₀ values of which are in good agreement with previously reported data. The reliability and reproducibility of the assay make it useful for in vitro screening for inhibitors of LOXs and, therefore, should accelerate drug discovery for clinical application.

Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays

Co-reporter:Guoping Hu ; Xi Li ; Xuan Zhang ; Yaozong Li ; Lei Ma ; Liu-Meng Yang ; Guixia Liu ; Weihua Li ; Jin Huang ; Xu Shen ; Lihong Hu ; Yong-Tang Zheng ;Yun Tang

Journal of Medicinal Chemistry 2012 Volume 55(Issue 22) pp:10108-10117

Publication Date(Web):October 9, 2012

DOI:10.1021/jm301226a

This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC50 values at 0.32 and 0.26 μM, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC50 = 1.81 μM). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.

Discovery of Diverse Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual Screening

Co-reporter:Yanyan Diao ; Weiqiang Lu ; Huangtao Jin ; Junsheng Zhu ; Le Han ; Minghao Xu ; Rui Gao ; Xu Shen ; Zhenjiang Zhao ; Xiaofeng Liu ; Yufang Xu ; Jin Huang ;Honglin Li

Journal of Medicinal Chemistry 2012 Volume 55(Issue 19) pp:8341-8349

Publication Date(Web):September 17, 2012

DOI:10.1021/jm300630p

This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC50 values ranging from 0.11 to 18.8 μM were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC50 value of 0.11 μM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC50 = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.

Natural products as a gold mine for selective matrix metalloproteinases inhibitors

Co-reporter:Liyan Wang, Xi Li, Shoude Zhang, Weiqiang Lu, Sha Liao, Xiaofeng Liu, Lei Shan, Xu Shen, Hualiang Jiang, Weidong Zhang, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry 2012 Volume 20(Issue 13) pp:4164-4171

Publication Date(Web):1 July 2012

DOI:10.1016/j.bmc.2012.04.063

Nineteen natural compounds with diverse structures are identified as potential MMPIs using structure-based virtual screening from 4000 natural products. Hydroxycinnamic acid or analogs of natural products are important for potent inhibitory and selectivity against MMPs, and the solvent effect in the S1′ pocket can affect the hydrophobic interactions and hydrogen bonds between MMPIs and MMPS, making MMPIs exhibit certain selectivity for a specific MMP isoenzyme. Furthermore, compound 5 can reduce the expression of both MMP-2 and active-MMP-9, and suppress the migration of MDA-MB-231 tumor cell in a wound healing assay, which may be further developed as an anticancer agent.

Synthesis, StructureActivity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors

Co-reporter:Deyan Wu;Fangfang Jin;Weiqiang Lu;Jin Zhu;Cui Li;Wei Wang;Yun Tang;Hualiang Jiang;Guixia Liu;Jian Li

Chemical Biology & Drug Design 2012 Volume 79( Issue 6) pp:897-906

Publication Date(Web):

DOI:10.1111/j.1747-0285.2012.01365.x

Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1–5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k–l, and 7a–e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure–activity relationships. Based on eight DPP-4 inhibitors (1–5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.

Cover Picture: Inhibitors of HIV-1 Integrase-Human LEDGF/p75 Interaction Identified from Natural Products via Virtual Screening (Chin. J. Chem. 12/2012)

Co-reporter:Guoping Hu;Xi Li;Yaozong Li;Xianqiang Sun;Guixia Liu;Weihua Li;Xu Shen;Yun Tang

Chinese Journal of Chemistry 2012 Volume 30( Issue 12) pp:

Publication Date(Web):

DOI:10.1002/cjoc.201290035

Inhibitors of HIV-1 Integrase-Human LEDGF/p75 Interaction Identified from Natural Products via Virtual Screening

Co-reporter:Guoping Hu;Xi Li;Yaozong Li;Xianqiang Sun;Guixia Liu;Weihua Li;Xu Shen;Yun Tang

Chinese Journal of Chemistry 2012 Volume 30( Issue 12) pp:2752-2758

Publication Date(Web):

DOI:10.1002/cjoc.201200897

Abstract

HIV-1 integrase (IN)-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor (LEDGF/p75) has been found to function as a cellular cofactor in this process. The LEDGF/p75-IN interaction hence represents an attractive target for anti-HIV therapy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen assays characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active compounds whose IC₅₀ values ranged from 0.56 to 14.55 µmol/L could be used as lead compounds for further investigation. This work confirmed that natural products are valuable resources for antiviral drug discovery.

Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent

Co-reporter:Huang Huang, Weiqiang Lu, Xi Li, Xiaoli Cong, Hongmei Ma, Xiaofeng Liu, Yu Zhang, Peng Che, Ruoqun Ma, Honglin Li, Xu Shen, Hualiang Jiang, Jin Huang, Jin Zhu

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 2) pp:958-962

Publication Date(Web):15 January 2012

DOI:10.1016/j.bmcl.2011.12.011

Resistance of malaria parasites has quickly developed to almost all used antimalarial drugs. Accordingly, the discovery of new effective drugs to counter the spread of malaria parasites that are resistant to existing agents, especially acting on multi-targets, is an urgent need. The cysteine protease falcipain-2 (FP-2) and dihydrofolate reductase (DHFR) play crucial roles in the Plasmodium life cycle. In this study, a series of first-gereration small molecular dual inhibitor of FP-2 and DHFR have been designed and synthesized based on the lead compound 1, which was randomly identified by screening FP-2 inhibitors in our laboratory. Six compounds (2f–g, 2j, and 2m–o) showed improved dual inhibitory activities against FP-2 (IC50 = 2.7–13.2 μM) and DHFR (IC50 = 1.8–19.8 μM), and the inhibitory capability of compound 2o against FP-2 and DHFR were increased ∼8 and ∼6 times than that of compound 1, respectively. Moreover, compound 2o exhibited moderate in vivo antimalarial activity in a dose dependent fashion, its safety and survival rate were slightly better than that of positive drug. The preliminary SAR was obtained, meanwhile, molecular modeling result provided the key structural information to maintain the dual inhibitory activity, and was helpful for future dual inhibitors design.

A fluorimetric assay for human reticulocyte 15-lipoxygenase-1 activity

Co-reporter:Weiqiang Lu, Xue Zhao, Shien Zou, Jin Huang

Analytical Biochemistry 2012 Volume 426(Issue 1) pp:66-68

Publication Date(Web):1 July 2012

DOI:10.1016/j.ab.2012.04.007

A rapid and sensitive fluorescence-based assay for the determination of human 15-lipoxygenase-1 (15-LOX-1) activity is described in this article. The assay utilizes the ability of 15-LOX-1-generated lipid hydroperoxides to oxidize nonfluorescent dihydrorhodamine 123, producing the highly fluorescent dye rhodamine 123. Formation of rhodamine 123 can be monitored through fluorescence spectroscopy using Ex/Em of 500 nm/536 nm. The IC50 values of three well-known 15-LOX-1 inhibitors, nordihydroguaiaretic acid, quercetin, and fisetin, were evaluated in 96- and 384-well formats, and they conform to previously reported data. We believe this assay can be broadly used for the discovery of novel lipoxygenase inhibitors.

Identification of diverse dipeptidyl peptidase IV inhibitors via structure-based virtual screening

Co-reporter:Cui Li;Weiqiang Lu;Chunhua Lu;Wen Xiao;Xu Shen

Journal of Molecular Modeling 2012 Volume 18( Issue 9) pp:4033-4042

Publication Date(Web):2012 September

DOI:10.1007/s00894-012-1394-3

Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of type II diabetes mellitus. Inhibition of DPP4 will improve glycemic control in such patients by preventing the rapid breakdown and thereby prolonging the physiological actions of incretin hormones. Known DPP4 inhibitors (including marketed drugs and those drug candidates) appear to share similar structural features: the cyanopyrrolidine moieties, the xanthenes/pyrimidine parts and amino-like linkages. In this study, a multi-step virtual screening strategy including both rigid and flexible docking was employed to search for novel structures with DPP4 inhibition. From SPECS database, consisting of over 190,000 commercially available compounds, 99 virtual hits were picked up and 15 of them were eventually identified to have DPP4 inhibitory activities at 5 ~ 50 μM. Diverse structures of our compounds were out of usual structural categories. Hence a pharmacophore model was built to further explore their common binding features on the enzyme. The results provided a new pathway for the discovery of DPP4 inhibitors and would be helpful for further optimization of DPP4 inhibitors.

Identification of old drugs as potential inhibitors of HIV-1 integrase – human LEDGF/p75 interaction via molecular docking

Co-reporter:Guoping Hu;Xi Li;Xianqiang Sun;Weiqiang Lu;Guixia Liu

Journal of Molecular Modeling 2012 Volume 18( Issue 12) pp:4995-5003

Publication Date(Web):2012 December

DOI:10.1007/s00894-012-1494-0

Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, human protein Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. LEDGF/p75-HIV-1 IN interaction represents an attractive target for anti-HIV therapy. In this study, approved drugs were investigated for the finding of potential inhibitors on this target. Via molecular docking against the LEDGF/p75-binding pocket of HIV-1 IN, 26 old drugs were selected from the DrugBank and purchased for bioassays. Among them, eight, namely Atorvastatin, Bumetanide, Candesartan, Carbidopa, Diclofenac, Diflunisal, Eprosartan, and Sulindac, were identified as potential inhibitors of LEDGF/p75- HIV-1 IN interaction, whose IC50 values ranged from 6.5 μM to 36.8 μM. In addition, Atorvastatin was previously reported to block HIV-1 replication and may have an important implication for the treatment of AIDS. Our results suggested a mechanism of action for the anti-HIV effects of Atorvastatin. This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery.

SHAFTS: A Hybrid Approach for 3D Molecular Similarity Calculation. 2. Prospective Case Study in the Discovery of Diverse p90 Ribosomal S6 Protein Kinase 2 Inhibitors To Suppress Cell Migration

Co-reporter:Weiqiang Lu ; Xiaofeng Liu ; Xianwen Cao ; Mengzhu Xue ; Kangdong Liu ; Zhenjiang Zhao ; Xu Shen ; Hualiang Jiang ; Yufang Xu ; Jin Huang ;Honglin Li

Journal of Medicinal Chemistry 2011 Volume 54(Issue 10) pp:3564-3574

Publication Date(Web):April 13, 2011

DOI:10.1021/jm200139j

We described a prospective application of ligand-based virtual screening program SHAFTS to discover novel inhibitors for p90 ribosomal S6 protein kinase 2 (RSK2). Taking the putative 3D conformations of two weakly binding RSK2 NTKD inhibitors as query templates, SHAFTS was used to perform 3D similarity based virtual screening because of a lack of crystal structure of RSK2 protein, thus leading to the identification of several novel scaffolds that would have been missed by conventional 2D fingerprint methods. The most potent hit compounds show low micromolar inhibitory activities against RSK2. In particular, one of the hit compounds exhibits potent antimigration activity against the MDA-MB-231 tumor cell. The results exemplified SHAFTS’ application in active enrichment and scaffold hopping, which is of general interest for lead identification in drug discovery endeavors and also provides novel scaffolds that lay the foundation for uncovering new RSK2 regulatory mechanisms.

Identification of Inhibitors against p90 Ribosomal S6 Kinase 2 (RSK2) through Structure-Based Virtual Screening with the Inhibitor-Constrained Refined Homology Model

Co-reporter:Shiliang Li, Yi Zhou, Weiqiang Lu, Ye Zhong, Wenlong Song, Kangdong Liu, Jin Huang, Zhenjiang Zhao, Yufang Xu, Xiaofeng Liu, and Honglin Li

Journal of Chemical Information and Modeling 2011 Volume 51(Issue 11) pp:2939-2947

Publication Date(Web):October 13, 2011

DOI:10.1021/ci2002445

P90 ribosomal S6 kinase 2 (RSK2), which was shown to be overexpressed in human cancers, is a serine/threonine kinase and a potential target for cancer treatment. RSK2 comprises two terminal kinase domains (NTKD and CTKD) that can be inhibited by binding with different types of inhibitors at the ATP binding sites. In the absence of a crystal structure of RSK2, we constructed a model for the 3D structure of the RSK2 NTKD by homology modeling and stepwise constrained refinement with the reported inhibitors using a molecular docking method. Structure-based virtual screening was subsequently performed against a library containing commercially available compounds using the refined model. This resulted in the identification of seven novel RSK2 inhibitors with IC50 values ranging from 2.4 to 14.45 μM.

Discovery of Potent Ligands for Estrogen Receptor β by Structure-Based Virtual Screening

Co-reporter:Jie Shen ; Chengfang Tan ; Yanyan Zhang ; Xi Li ; Weihua Li ; Jin Huang ; Xu Shen ;Yun Tang

Journal of Medicinal Chemistry 2010 Volume 53(Issue 14) pp:5361-5365

Publication Date(Web):June 16, 2010

DOI:10.1021/jm100369g

With virtual screening based on a structure optimized through molecular dynamics (MD) and bioassays, 18 potent ligands of estrogen receptor (ER) β were discovered from 70 purchased compounds here. Among them, dual profile was observed in two ligands (1a and 1b), as agonists for ERβ and antagonists for ERα, and they might serve as lead compounds for selective ER modulators. The results also suggest that structures optimized through MD are applicable to lead discovery.

Butyl 4-(butyryloxy)benzoate functions as a new selective estrogen receptor β agonist and induces GLUT4 expression in CHO-K1 cells

Co-reporter:Zhaohu Lin, Hong Shen, Jin Huang, Shuai Chen, Lili Chen, Jing Chen, Guixia Liu, Hualiang Jiang, Xu Shen

The Journal of Steroid Biochemistry and Molecular Biology (May 2008) Volume 110(Issues 1–2) pp:150-156

Publication Date(Web):1 May 2008

DOI:10.1016/j.jsbmb.2008.03.028

Estrogen receptors (ERs) belong to nuclear hormone receptor superfamily and can be activated by estrogens and regulate many target genes. Two ER isoforms, ERα and ERβ have been discovered to date and ERβ was indicated to involve in anti-inflammatory and anti-diabetogenic effects. Recently, some studies also demonstrated an association between ERβ and GLUT4 expression. The development of selective ERβ ligand has facilitated probing its novel biological functions and clinical benefits. In this work, a new ERβ selective agonist, butyl 4-(butyryloxy)benzoate (DCW234), was discovered as investigated by surface plasmon resonance (SPR) technology, yeast two-hybrid and cell-based transcription-based assays. SPR results demonstrated that DCW234 has a higher binding affinity against ERβ over ERα and induces a strong and selective stimulation on ERβ/SRC1 interaction, which could be efficiently blocked by Tamoxifen. Meanwhile, the yeast two-hybrid technology-based assay indicated that DCW234 exhibits a higher agonistic activity (∼13-fold) in stimulating ERβ ligand-binding domain (LBD) interaction with SRC1 (EC50 = 2.5 μM) than ERα-LBD/SRC1 interaction (EC50 = 32.7 μM). The cell-based transcriptional assay further proved the potency and selectivity of DCW234. Moreover, DCW234 was found to be able to induce GLUT4 expression in CHO-K1 cell. The discovered DCW234 might be hopefully developed as a potential lead compound for further research.

Butyl 4-(butyryloxy)benzoate functions as a new selective estrogen receptor β agonist and induces GLUT4 expression in CHO-K1 cells

Co-reporter:Zhaohu Lin, Hong Shen, Jin Huang, Shuai Chen, Lili Chen, Jing Chen, Guixia Liu, Hualiang Jiang, Xu Shen

The Journal of Steroid Biochemistry and Molecular Biology (May 2008) Volume 110(Issues 1–2) pp:150-156

Publication Date(Web):1 May 2008

DOI:10.1016/j.jsbmb.2008.03.028

HL005—A new selective PPARγ antagonist specifically inhibits the proliferation of MCF-7

Co-reporter:Weiqiang Lu, Peng Che, Yanyan Zhang, Honglin Li, Shien Zou, Jin Zhu, Jing Deng, Xu Shen, Hualiang Jiang, Jian Li, Jin Huang

The Journal of Steroid Biochemistry and Molecular Biology (April 2011) Volume 124(Issues 3–5) pp:112-120

Publication Date(Web):1 April 2011

DOI:10.1016/j.jsbmb.2011.01.019

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear transcription factor which is involved in many diseases, such as diabetes, inflammation, dyslipidemia, hypertension, and cancer. Recently, there are many reports showing that PPARγ agonists have preclinical and clinical anticancer activity, with relatively few reports on anticancer effects of PPARγ antagonists. From our compound library, a novel 3-thiazolinone-modified benzoic acid derivative HL005 is found as PPARγ selective ligand through SPR analysis (KD = 0.21 μM), yeast two-hybrid results suggest that HL005 antagonize the potent PPARγ agonist rosiglitazone-induced recruitment of the coactivator for PPARγ (IC50 = 7.97 μM). Different from the most reported PPARγ antagonist, HL005 can inhibit the proliferation of MCF-7 cell line in a concentration-dependent manner and induce cell cycle arrest at G2/M phase, other than interference with cell adhesion. In order to study the binding mode of this compound, three derivatives are synthesized to get more detail about the structure–activity relationship, molecular docking and the NMR spectra indicate that similar to most PPARγ ligand, the carboxylic acid group is an important moiety for HL005 and contributes strong interaction with PPARγ.Research highlights► A novel 3-thiazolinone-modified benzoic acid derivative (HL005), was a potent PPARγ specific antagonist. ► HL005 can significantly inhibit the proliferation of MCF-7 cancer cell and caused cell cycle arrest at G2/M phase. ► The carboxylic acid group is an important moiety for HL005 and contributes strong interaction with PPARγ.