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Current Strategies and Applications for Precision Drug Design

Chen Wang, Pan Xu, Luyu Zhang, Jing Huang, Kongkai Zhu, Cheng Luo
<span title="2018-07-18">2018</span> <i title="Frontiers Media SA"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/qigargnicncadmdn56ei23yjnu" style="color: black;">Frontiers in Pharmacology</a> </i> &nbsp;
., 2018; Zhu et al., 2018) .  ...  Copyright © 2018 Wang, Xu, Zhang, Huang, Zhu and Luo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3389/fphar.2018.00787">doi:10.3389/fphar.2018.00787</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30072901">pmid:30072901</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC6060444/">pmcid:PMC6060444</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/wsjxqle6ozhmhocmwfz6nd4x6i">fatcat:wsjxqle6ozhmhocmwfz6nd4x6i</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200209193155/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6060444&amp;blobtype=pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/b9/74/b974589bdd14aeee0a66c1ef06f91e29fd85072a.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3389/fphar.2018.00787"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> frontiersin.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060444" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Discovery of Novel PRMT5 Inhibitors by Virtual Screening and Biological Evaluations

Hongrui Tao, Xue Yan, Kongkai Zhu, Hua Zhang
<span title="2019-04-01">2019</span> <i title="Pharmaceutical Society of Japan"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/bliguyxhonfb7ghuykxgtg3oqe" style="color: black;">Chemical and pharmaceutical bulletin</a> </i> &nbsp;
As an important epigenetics related enzyme, protein arginine methyltransferase 5 (PRMT5) has been confirmed as an anticancer therapeutic target in recent years. Among all the reported PRMT5 inhibitors, two small molecules (GSK-3326595 and JNJ-64619178) are currently being assessed in clinical trial. In this study, 40 PRMT5 inhibitor candidates were purchased from SPECS database supplier according to the pharmacophore and molecular docking based virtual screening results. Alpha linked
more &raquo; ... nt assay (LISA) methylation assay was performed to test their inhibitory activity against PRMT5. The in vitro enzymatic assay results indicated that four compounds (2, 4, 10 and 37) showed PRMT5 inhibitory activity, while 4 and 10 displayed the most potent activity with IC 50 values of 8.1 1.1 and 6.5 0.6 µM, respectively. The inhibitory activity results of 20 extra analogs of 4 further confirmed the potency of this scaffold. As expected, compounds 4 and 10 exhibited moderate anti-proliferative activity against mantle cell lymphoma Jeko-1 and leukemia cell MV4-11. Besides, Western blot assay results showed that 4 could reduce the H4R3me2s level in a dose-dependent manner, indicating that it could inhibit the activity of PRMT5 in cellular context. Detailed interactions between 4 and PRMT5 were characterized by binding mode analysis through molecular docking. The compounds discovered in this study will inspire medicinal chemists to further explore this series of PRMT5 inhibitors.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1248/cpb.c18-00980">doi:10.1248/cpb.c18-00980</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/7pr4cox75bbxlehdsq6npt3w5e">fatcat:7pr4cox75bbxlehdsq6npt3w5e</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190503160643/https://www.jstage.jst.go.jp/article/cpb/67/4/67_c18-00980/_pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/f6/8c/f68c875107057109903ac7215a9ab84a47f88330.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1248/cpb.c18-00980"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> Publisher / doi.org </button> </a>

Bioactive Pyridone Alkaloids from a Deep-Sea-Derived Fungus Arthrinium sp. UJNMF0008

Jie Bao, Huijuan Zhai, Kongkai Zhu, Jin-Hai Yu, Yuying Zhang, Yinyin Wang, Cheng-Shi Jiang, Xiaoyong Zhang, Yun Zhang, Hua Zhang
<span title="2018-05-22">2018</span> <i title="MDPI AG"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/ec2qn47apbbfjgxx4e2oivikr4" style="color: black;">Marine Drugs</a> </i> &nbsp;
Eight new 4-hydroxy-2-pyridone alkaloids arthpyrones D-K (1-8), along with two known analogues apiosporamide (9) and arthpyrone B (10), were isolated from a deep-sea-derived fungus Arthrinium sp. UJNMF0008. The structures of the isolated compounds were elucidated on the basis of spectroscopic methods with that of 1 being established by chemical transformation and X-ray diffraction analysis. Compounds 1 and 2 bore an ester functionality linking the pyridone and decalin moieties first reported in
more &raquo; ... this class of metabolites, while 3 and 4 incorporated a rare natural hexa-or tetrahydrobenzofuro[3,2-c]pyridin-3(2H)-one motif. Compounds 3-6 and 9 exhibited moderate to significant antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus with IC 50 values ranging from 1.66-42.8 µM, while 9 displayed cytotoxicity against two human osteosarcoma cell lines (U2OS and MG63) with IC 50 values of 19.3 and 11.7 µM, respectively. basis of comprehensive spectroscopic analyses, and their absolute configurations were assigned by different means including ECD comparison, chemical transformation and X-ray crystallography. All the isolates were tested for their antimicrobial, cytotoxic and acetylcholinesterase (AChE) inhibitory activities. The assay results established that 3-6 and 9 were mild to significant antibacterial agents against Mycobacterium smegmatis and S. aureus, while 9 showed moderate cytotoxicity against two human osteosarcoma cell lines U2OS and MG63.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/md16050174">doi:10.3390/md16050174</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/29786655">pmid:29786655</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC5983305/">pmcid:PMC5983305</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/iyydzhhkbneltmjslphwtnitfq">fatcat:iyydzhhkbneltmjslphwtnitfq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190309151900/http://pdfs.semanticscholar.org/fb64/7d49201f969c36cb5a5298fa87241e468b4d.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/fb/64/fb647d49201f969c36cb5a5298fa87241e468b4d.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/md16050174"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> mdpi.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983305" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

New Octadecanoid Enantiomers from the Whole Plants of Plantago depressa

Xiu-Qing Song, Kongkai Zhu, Jin-Hai Yu, Qianqian Zhang, Yuying Zhang, Fei He, Zhi-Qiang Cheng, Cheng-Shi Jiang, Jie Bao, Hua Zhang
<span title="2018-07-14">2018</span> <i title="MDPI AG"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/dstyyzbt45gknhqqjsh45p55h4" style="color: black;">Molecules</a> </i> &nbsp;
In this study, 19 octadecanoid derivatives—four pairs of enantiomers (1–8), two racemic/scalemic mixtures (9–10), and nine biosynthetically related analogues—were obtained from the ethanolic extract of a Chinese medicinal plant, Plantago depressa Willd. Their structures were elucidated on the basis of detailed spectroscopic analyses, with the absolute configurations of the new compounds assigned by time-dependent density functional theory (TD-DFT)-based electronic circular dichroism (ECD)
more &raquo; ... ations. Six of them (1, 3–6, and 9) were reported for the first time, while 2, 7, and 8 have been previously described as derivatives and are currently obtained as natural products. Our bioassays have established that selective compounds show in vitro anti-inflammatory activity by inhibiting lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules23071723">doi:10.3390/molecules23071723</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30011919">pmid:30011919</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/fbdsw72qa5bhteieajiecjq4z4">fatcat:fbdsw72qa5bhteieajiecjq4z4</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190303094727/http://pdfs.semanticscholar.org/b354/dc386709f1f0abd234696a8f1f58c78b4d5f.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/b3/54/b354dc386709f1f0abd234696a8f1f58c78b4d5f.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules23071723"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> mdpi.com </button> </a>

Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1

Ruihan Zhang, Xin Li, Zhongjie Liang, Kongkai Zhu, Junyan Lu, Xiangqian Kong, Sisheng Ouyang, Lin Li, Yujun George Zheng, Cheng Luo, Albert Jeltsch
<span title="2013-08-20">2013</span> <i title="Public Library of Science (PLoS)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/s3gm7274mfe6fcs7e3jterqlri" style="color: black;">PLoS ONE</a> </i> &nbsp;
Protein arginine methyltransferase 1 (PRMT1), the major arginine asymmetric dimethylation enzyme in mammals, is emerging as a potential drug target for cancer and cardiovascular disease. Understanding the catalytic mechanism of PRMT1 will facilitate inhibitor design. However, detailed mechanisms of the methyl transfer process and substrate deprotonation of PRMT1 remain unclear. In this study, we present a theoretical study on PRMT1 catalyzed arginine dimethylation by employing molecular
more &raquo; ... (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) calculation. Ternary complex models, composed of PRMT1, peptide substrate, and S-adenosyl-methionine (AdoMet) as cofactor, were constructed and verified by 30-ns MD simulation. The snapshots selected from the MD trajectory were applied for the QM/MM calculation. The typical S N 2-favored transition states of the first and second methyl transfers were identified from the potential energy profile. Deprotonation of substrate arginine occurs immediately after methyl transfer, and the carboxylate group of E144 acts as proton acceptor. Furthermore, natural bond orbital analysis and electrostatic potential calculation showed that E144 facilitates the charge redistribution during the reaction and reduces the energy barrier. In this study, we propose the detailed mechanism of PRMT1catalyzed asymmetric dimethylation, which increases insight on the small-molecule effectors design, and enables further investigations into the physiological function of this family.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0072424">doi:10.1371/journal.pone.0072424</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/23977297">pmid:23977297</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC3748068/">pmcid:PMC3748068</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/ikomhl7k3be5dnzfpb2wm5ar2y">fatcat:ikomhl7k3be5dnzfpb2wm5ar2y</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20171008045518/http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0072424&amp;type=printable" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/f1/b8/f1b81bc7d8004c543679fd1695bb9e8446a4faac.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1371/journal.pone.0072424"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> plos.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748068" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Targeting PRMT5 Activity Inhibits the Malignancy of Hepatocellular Carcinoma by Promoting the Transcription of HNF4α

Bai-Nan Zheng, Chen-Hong Ding, Shi-Jie Chen, Kongkai Zhu, Jingwei Shao, Jifeng Feng, Wen-Ping Xu, Ling-Yan Cai, Chang-Peng Zhu, Wenhu Duan, Jin Ding, Xin Zhang (+2 others)
<span title="2019-04-13">2019</span> <i title="Ivyspring International Publisher"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/7doy657d75hpdkozsdchkxsg34" style="color: black;">Theranostics</a> </i> &nbsp;
Liver cancer stem cells (LCSCs) are responsible for the initiation, progression and chemoresistance of liver cancer. However, no agent targeting LCSC is available in the clinic to date. Here, we investigated the effects of targeting protein arginine methyltransferase 5 (PRMT5), an epigenetic regulator, on LCSCs and HCC using a novel PRMT5 inhibitor DW14800. Methods: Tumor spheroid formation culture was used to enrich LCSCs and assess their self-renewal capability. Human alpha-1-antitrypsin
more &raquo; ... ) ELISA, acetylated low-density lipoprotein (ac-LDL) uptake, periodic acid-Schiff (PAS) reactions and senescence associated β-galactosidase (SA-β-gal) activity assays were performed to examine the differentiation status of HCC cells. The effects of DW14800 on HCC malignancy were assessed in HCC cell lines and on an HCC xenograft model in mice. Chromatin immunoprecipitation was applied to clarify the transcriptional regulation of HNF4α by PRMT5-mediated Histone H4 arginine-3 symmetrical dimethylation (H4R3me2s). Results: Quantitative real-time PCR revealed that the expression of PRMT5 was upregulated in LCSCs. DW14800 specifically decreased the symmetrical dimethylation of arginine residues in HCC cells. Treatment of DW14800 suppressed the self-renewal capacity of LCSCs while re-establishing hepatocyte-specific characteristics in HCC cells. DW14800 displayed antitumor effects in HCC cells in vitro and in xenograft HCC in vivo. Importantly, ChIP assay showed that PRMT5 and H4R3me2s bound to the promoter region of HNF4α gene, and DW14800 increased the expression of HNF4α via reducing the H4R3me2s levels and enhancing the transcription of HNF4α. Conclusions: Our data revealed the significance of targeting PRMT5 activity in LCSC elimination and HCC differentiation, and proposed that DW14800 may represent a promising therapeutic agent for HCC in the clinic.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.7150/thno.32344">doi:10.7150/thno.32344</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/31131056">pmid:31131056</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC6525986/">pmcid:PMC6525986</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/6jquj7ils5dv5laljsstg54kuy">fatcat:6jquj7ils5dv5laljsstg54kuy</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190429160034/http://www.thno.org/v09p2606.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/0c/d7/0cd7a0c855f350dd3290a518c23e550cb5c13f78.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.7150/thno.32344"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525986" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

Cheng-Shi Jiang, Chun-Lin Zhuang, Kongkai Zhu, Juan Zhang, Luis Alexandre Muehlmann, João Paulo Figueiró Longo, Ricardo Bentes Azevedo, Wen Zhang, Ning Meng, Hua Zhang
<span title="2018-04-25">2018</span> <i title="Figshare"> Figshare </i> &nbsp;
A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor ZJ01 was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. ZJ01 could in vitro trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, ZJ01 suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2
more &raquo; ... cardiac cells. Moreover, in an in vivo mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, ZJ01 demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound ZJ01 is a promising drug lead for septic cardiomyopathy treatment. ZJ01 was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by in vitro and in vivo experiments.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.6084/m9.figshare.6182003">doi:10.6084/m9.figshare.6182003</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/nuurpaslffb2hafdew35f3xazi">fatcat:nuurpaslffb2hafdew35f3xazi</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200229213231/https://s3-eu-west-1.amazonaws.com/pstorage-tf-iopjsd8797887/11198597/ienz_a_1461856_sm1140.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/66/21/66216a3c2fc35cdd147b6c5f985fa9d7ff09d3a1.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.6084/m9.figshare.6182003"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> figshare.com </button> </a>

Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer

Jianhua Mao, Lie Ma, Yan Shen, Kongkai Zhu, Ru Zhang, Wenda Xi, Zheng Ruan, Cheng Luo, Zhu Chen, Xiaodong Xi, Saijuan Chen
<span title="2018-09-20">2018</span> <i title="Springer Nature America, Inc"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/glpuqq6s5zas3iz6q32stxybcq" style="color: black;">Cell Death and Disease</a> </i> &nbsp;
Non-small cell lung cancer (NSCLC) is characterized by hyperexpression and/or gain-of-function mutations of the epidermal growth factor receptor (EGFR), resulting in an elevated overall kinase activity. Gefitinib is remarkably effective in patients with the L858R or ΔE746-A750-mutated of EGFR. However, drug resistance tends to develop because of the emergence of T790M mutation on EGFR. New strategies other than repressing kinase activity are thus required to treat NSCLC, thereby circumventing
more &raquo; ... e resistance. In this study, arsenic trioxide (ATO) at 2 μM significantly inhibited the proliferation of the gefitinib-resistant NCI-H1975 cells of the EGFR L858R/T790M mutant compared with a modest inhibition in the gefitinib-sensitive HCC827 cells of ΔE746-A750 mutant and A549 cells of wild-type EGFR. Moreover, ATO significantly inhibited the overall kinase activity of EGFR primarily through quantitatively diminishing the EGFR in NCI-H1975 cells to an extent comparable with that reached by gefitinib in HCC827 cells. Furthermore, ATO promoted autophagic degradation of EGFR in NSCLC cells by directly binding to P62, which interacted with EGFR, preferentially the L858R/T790M mutant providing a plausible explanation for a more favorable effect of ATO on NCI-H1975 cells. Accordingly, the effect of ATO was further confirmed in the NSCLC xenograft mouse models. Our results reveal a new target for ATO with a unique molecular mechanism, i.e., ATO suppresses the overall catalytic potential of EGFR, significantly those with the L858R/T790M mutant in NCI-H1975 cells, through an autophagic degradation by interacting with P62. This study potentially offers an innovative therapeutic avenue for the NSCLC with L858R/T790Mmutated EGFR.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/s41419-018-0998-7">doi:10.1038/s41419-018-0998-7</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30237564">pmid:30237564</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC6147786/">pmcid:PMC6147786</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/gk6v4blfqzguzitqv6yiz74duu">fatcat:gk6v4blfqzguzitqv6yiz74duu</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200206071901/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6147786&amp;blobtype=pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/0b/fb/0bfb76957570960ea8eeb7e07bce6318f6b77511.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1038/s41419-018-0998-7"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> Publisher / doi.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147786" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Design, Synthesis and Biological Evaluation of Novel Coumarin-Based Hydroxamate Derivatives as Histone Deacetylase (Hdac) Inhibitors with Antitumor Activities

Feifei Yang, Na Zhao, Jiali Song, Kongkai Zhu, Cheng-shi Jiang, Peipei Shan, Hua Zhang
<span title="2019-07-15">2019</span> <i title="MDPI AG"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/dstyyzbt45gknhqqjsh45p55h4" style="color: black;">Molecules</a> </i> &nbsp;
A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward
more &raquo; ... human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules24142569">doi:10.3390/molecules24142569</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/31311163">pmid:31311163</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC6680717/">pmcid:PMC6680717</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/gncdnspf4be23fkysybzcgglwe">fatcat:gncdnspf4be23fkysybzcgglwe</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200209010023/https://res.mdpi.com/d_attachment/molecules/molecules-24-02569/article_deploy/molecules-24-02569.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/fd/ce/fdcef8e37891b3b2b1932da2584cbb837ba03f1f.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules24142569"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> mdpi.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680717" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis

Lu Jin, Fei Ye, Dan Zhao, Shijie Chen, Kongkai Zhu, Mingyue Zheng, Ren-Wang Jiang, Hualiang Jiang, Cheng Luo
<span title="">2014</span> <i title="Hindawi Limited"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/icbhosh775h7bgzgot6avm3cua" style="color: black;">BioMed Research International</a> </i> &nbsp;
DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify the genetic information hidden in DNA. To investigate the conversion process of base flipping in the HhaI methyltransferase (M.HhaI), we performed different molecular simulation approaches on
more &raquo; ... NA-S-adenosylhomocysteine ternary complex. The results demonstrate that the nonspecific binding of DNA to M.HhaI is initially induced by electrostatic interactions. Differences in chemical environment between the major and minor grooves determine the orientation of DNA. Gln237 at the target recognition loop recognizes the GCGC base pair from the major groove side by hydrogen bonds. In addition, catalytic loop motion is a key factor during this process. Our study indicates that base flipping is likely to be an "induced-fit" process. This study provides a solid foundation for future studies on the discovery and development of mechanism-based DNA methyltransferases regulators.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1155/2014/304563">doi:10.1155/2014/304563</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/25045662">pmid:25045662</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4090504/">pmcid:PMC4090504</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/uau4o7lombeahmi5x4jf6umfhe">fatcat:uau4o7lombeahmi5x4jf6umfhe</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20170810215945/http://selfdeterminationtheory.org/SDT/documents/2005_IsenReeve_MO.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/77/8f/778f5b7bfc3e6580c52f8f33b4bfce83c7d4b44d.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1155/2014/304563"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> hindawi.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090504" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Discovery of New α-Glucosidase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation

Shan-Kui Liu, Haifang Hao, Yuan Bian, Yong-Xi Ge, Shengyuan Lu, Hong-Xu Xie, Kai-Ming Wang, Hongrui Tao, Chao Yuan, Juan Zhang, Jie Zhang, Cheng-Shi Jiang (+1 others)
<span title="2021-03-08">2021</span> <i title="Frontiers Media SA"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/r7gejflxajhbzghowl6qigukjq" style="color: black;">Frontiers in Chemistry</a> </i> &nbsp;
Copyright © 2021 Liu, Hao, Bian, Ge, Lu, Xie, Wang, Tao, Yuan, Zhang, Zhang, Jiang and Zhu.  ... 
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3389/fchem.2021.639279">doi:10.3389/fchem.2021.639279</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/33763406">pmid:33763406</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC7982526/">pmcid:PMC7982526</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/c6xu65qjtzfl5cwkuld6xabn2m">fatcat:c6xu65qjtzfl5cwkuld6xabn2m</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210313110446/https://fjfsdata01prod.blob.core.windows.net/articles/files/639279/pubmed-zip/.versions/1/.package-entries/fchem-09-639279.pdf?sv=2018-03-28&amp;sr=b&amp;sig=YCKtjpwfXAxstsdtVweSXupBqy6%2BQeCsXjO6K4208co%3D&amp;se=2021-03-13T11%3A05%3A15Z&amp;sp=r&amp;rscd=attachment%3B%20filename%2A%3DUTF-8%27%27fchem-09-639279.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/33/54/335454ef604e2913581c29df3b2324aa3ae5c50a.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3389/fchem.2021.639279"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> frontiersin.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982526" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Single-molecule FRET and conformational analysis of beta-arrestin-1 through genetic code expansion and Se-Click reaction

Ming-Jie Han, Qing-Tao He, Mengyi Yang, Chao Chen, Yirong Yao, Xiaohong Liu, Yuchuan Wang, Zhong-liang Zhu, Kongkai Zhu, Chang-Xiu Qu, Fan Yang, Cheng Hu (+5 others)
<span title="">2021</span> <i title="Royal Society of Chemistry (RSC)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/lnaynun4fzdepmirohmumo7whu" style="color: black;">Chemical Science</a> </i> &nbsp;
Single-molecule Förster resonance energy transfer (smFRET) is a powerful tool for investigating the dynamic properties of biomacromolecules. However, the success of protein smFRET relies on the precise and efficient labeling...
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1039/d1sc02653d">doi:10.1039/d1sc02653d</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/s5tje4uj2ve7nlqxvwy5mtscpq">fatcat:s5tje4uj2ve7nlqxvwy5mtscpq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20210603005435/https://pubs.rsc.org/en/content/articlepdf/2021/sc/d1sc02653d" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/80/3e/803e464d8d2e5b7b7e446b44ca3f6e5d4604cd7b.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1039/d1sc02653d"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> Publisher / doi.org </button> </a>

Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

Cheng-Shi Jiang, Yong-Xi Ge, Zhi-Qiang Cheng, Yin-Yin Wang, Hong-Rui Tao, Kongkai Zhu, Hua Zhang
<span title="2019-07-15">2019</span> <i title="MDPI AG"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/dstyyzbt45gknhqqjsh45p55h4" style="color: black;">Molecules</a> </i> &nbsp;
In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed
more &raquo; ... improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules24142568">doi:10.3390/molecules24142568</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/31311169">pmid:31311169</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC6680840/">pmcid:PMC6680840</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/qvifndbutzcm5b473pzjiclxiq">fatcat:qvifndbutzcm5b473pzjiclxiq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20200212130015/https://res.mdpi.com/d_attachment/molecules/molecules-24-02568/article_deploy/molecules-24-02568.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/f1/ab/f1ab49bf07c4637b483fb1b9a5d89d777e89a09c.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/molecules24142568"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> mdpi.com </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680840" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction

Xinlei Zhang, Sisheng Ouyang, Xiangqian Kong, Zhongjie Liang, Junyan Lu, Kongkai Zhu, Dan Zhao, Mingyue Zheng, Hualiang Jiang, Xin Liu, Ronen Marmorstein, Cheng Luo
<span title="2014-02-19">2014</span> <i title="American Chemical Society (ACS)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/ah52wn6qqbeilcx7mb5h3ozbeu" style="color: black;">Journal of Physical Chemistry B</a> </i> &nbsp;
The transcriptional coactivator and histone acetyltransferase (HAT) p300 acetylates the four core histones and other transcription factors to regulate a plethora of fundamental biological processes including cell growth, development, oncogenesis and apoptosis. Recent structural and biochemical studies on the p300 HAT domain revealed a Theorell-Chance, or "hit-and-run", catalytic mechanism. Nonetheless, the chemical mechanism of the entire reaction process including the proton transfer (PT)
more &raquo; ... e and consequent acetylation reaction route remains unclear. In this study, a combined computational strategy consisting of molecular modeling, molecular dynamic (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) simulation was applied to elucidate these important issues. An initial p300/H3/Ac-CoA complex structure was modeled and optimized using a 100 ns MD simulation. Residues that play important roles in substrate binding and the acetylation reaction were comprehensively investigated. For the first time, these studies reveal a plausible PT scheme consisting of Y1394, D1507, and a conserved crystallographic water molecule, with all components of the scheme being stable during the MD simulation and the energy barrier low for PT to occur. The two-dimensional potential energy surface for the nucleophilic attack process was also calculated. The comparison of potential energies for two possible elimination half-reaction mechanisms revealed that Y1467 reprotonates the coenzyme-A leaving group to form product. This study provides new insights into the detailed catalytic mechanism of p300 and has important implications for the discovery of novel small molecule regulators for p300.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1021/jp409778e">doi:10.1021/jp409778e</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/24521098">pmid:24521098</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC4037238/">pmcid:PMC4037238</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/s24njii7uvgfrlz4pioow3ppwe">fatcat:s24njii7uvgfrlz4pioow3ppwe</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20191107023516/http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4037238&amp;blobtype=pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/23/71/237125debcc37b82981e96e967e2523726a4262b.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.1021/jp409778e"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="external alternate icon"></i> acs.org </button> </a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037238" title="pubmed link"> <button class="ui compact blue labeled icon button serp-button"> <i class="file alternate outline icon"></i> pubmed.gov </button> </a>

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors

Zhi-Qiang Cheng, Jia-Li Song, Kongkai Zhu, Juan Zhang, Cheng-Shi Jiang, Hua Zhang
<span title="2018-08-21">2018</span> <i title="MDPI AG"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/ec2qn47apbbfjgxx4e2oivikr4" style="color: black;">Marine Drugs</a> </i> &nbsp;
A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis
more &raquo; ... gested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer's disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/md16090293">doi:10.3390/md16090293</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/30134630">pmid:30134630</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/cfeubvmub5f5hogz3gi3wq6ekq">fatcat:cfeubvmub5f5hogz3gi3wq6ekq</a> </span>
<a target="_blank" rel="noopener" href="https://web.archive.org/web/20190304004302/http://pdfs.semanticscholar.org/bdf9/e0c5b233067c9c9f0e422e3dc90d8d18bac5.pdf" title="fulltext PDF download" data-goatcounter-click="serp-fulltext" data-goatcounter-title="serp-fulltext"> <button class="ui simple right pointing dropdown compact black labeled icon button serp-button"> <i class="icon ia-icon"></i> Web Archive [PDF] <div class="menu fulltext-thumbnail"> <img src="https://blobs.fatcat.wiki/thumbnail/pdf/bd/f9/bdf9e0c5b233067c9c9f0e422e3dc90d8d18bac5.180px.jpg" alt="fulltext thumbnail" loading="lazy"> </div> </button> </a> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.3390/md16090293"> <button class="ui left aligned compact blue labeled icon button serp-button"> <i class="unlock alternate icon" style="background-color: #fb971f;"></i> mdpi.com </button> </a>
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