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Showing papers by "Kaixian Chen published in 2018"


Journal ArticleDOI
TL;DR: Recently, due to the strong generalization ability and powerful feature extraction capability, deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules, which will further promote the application of AI technologies in the field of drug design.
Abstract: Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology, the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials. Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence (AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening, activity scoring, quantitative structure-activity relationship (QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability, deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules, which will further promote the application of AI technologies in the field of drug design.

109 citations


Journal ArticleDOI
TL;DR: Regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC, and is revealed as a direct transactivation target of H NF1α in HCC cells and involved in the anti-HCC effect.
Abstract: Our previous study has demonstrated that hepatocyte nuclear factor 1α (HNF1α) exerts potent therapeutic effects on hepatocellular carcinoma (HCC). However, the molecular mechanisms by which HNF1α reverses HCC malignancy need to be further elucidated. lncRNA microarray was performed to identify the long noncoding RNAs (lncRNAs) regulated by HNF1α. Chromatin immunoprecipitation and luciferase reporter assays were applied to clarify the mechanism of the transcriptional regulation of HNF1α to HNF1A antisense RNA 1 (HNF1A-AS1). The effect of HNF1A-AS1 on HCC malignancy was evaluated in vitro and in vivo. RNA pulldown, RNA-binding protein immunoprecipitation and the Bio-Layer Interferometry assay were used to validate the interaction of HNF1A-AS1 and Src homology region 2 domain-containing phosphatase 1 (SHP-1). HNF1α regulated the expression of a subset of lncRNAs in HCC cells. Among these lncRNAs, the expression levels of HNF1A-AS1 were notably correlated with HNF1α levels in HCC cells and human HCC tissues. HNF1α activated the transcription of HNF1A-AS1 by directly binding to its promoter region. HNF1A-AS1 inhibited the growth and the metastasis of HCC cells in vitro and in vivo. Moreover, knockdown of HNF1A-AS1 reversed the suppressive effects of HNF1α on the migration and invasion of HCC cells. Importantly, HNF1A-AS1 directly bound to the C-terminal of SHP-1 with a high binding affinity (KD = 59.57 ± 14.29 nM) and increased the phosphatase activity of SHP-1. Inhibition of SHP-1 enzymatic activity substantially reversed the HNF1α- or HNF1A-AS1-induced reduction on the metastatic property of HCC cells. Our data revealed that HNF1A-AS1 is a direct transactivation target of HNF1α in HCC cells and involved in the anti-HCC effect of HNF1α. HNF1A-AS1 functions as phosphatase activator through the direct interaction with SHP-1. These findings suggest that regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC.

57 citations


Journal ArticleDOI
TL;DR: This review summarizes the main advancements in computational methodology development, which are illustrated by several successful applications in CBDD, and discusses the current major challenges and future directions in the field.
Abstract: Over the past quarter of a century, there has been rapid development in structural biology, which now can provide solid evidence for understanding the functions of proteins. Concurrently, computational approaches with particular relevance to the chemical biology and drug design (CBDD) field have also incrementally and steadily improved. Today, these methods help elucidate detailed working mechanisms and accelerate the discovery of new chemical modulators of proteins. In recent years, integrating computational simulations and predictions with experimental validation has allowed for more effective explorations of the structure, function and modulation of important therapeutic targets. In this review, we summarize the main advancements in computational methodology development, which are then illustrated by several successful applications in CBDD. Finally, we conclude with a discussion of the current major challenges and future directions in the field.

32 citations


Journal ArticleDOI
TL;DR: A series of novel marine phidianidine derivatives, displaying the most promising inhibitory effects and low toxicities, were found to possess immune-regulatory activities upon cross-linking of T cell receptor (TCR) and B cell receptors (BCR) on purified T and B cells, respectively.
Abstract: A series of novel marine phidianidine derivatives were designed, synthesized, and evaluated for their immunosuppressive activities during our search of potential immunosuppressive agents with high efficacy and low toxicity from marine sources. These compounds were tested for their inhibitory activity on Con A-induced T cell and lipopolysaccharide-induced B cell proliferation. Compounds 14a and 18c, displaying the most promising inhibitory effects and low toxicities, were further found to possess immune-regulatory activities upon cross-linking of T cell receptor (TCR) and B cell receptor (BCR) on purified T and B cells, respectively.

26 citations


Journal ArticleDOI
TL;DR: An AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors was developed and the physicochemical conditions including pH, salt concentrations and detergent levels were optimized and DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMAR CA2-related functional studies.
Abstract: SMARCA2 is a critical catalytic subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complexes. Dysregulation of SMARCA2 is associated with several diseases, including some cancers. SMARCA2 is multi-domain protein containing a bromodomain (BRD) that specifically recognizes acetylated lysine residues in histone tails, thus playing an important role in chromatin remodeling. Many potent and specific inhibitors targeting other BRDs have recently been discovered and have been widely used for cancer treatments and biological research. However, hit discovery targeting SMARCA2-BRD is particularly lacking. To date, there is a paucity of reported high-throughput screening (HTS) assays targeting the SMARCA2-BRD interface. In this study, we developed an AlphaScreen HTS system for the discovery of SMARCA2-BRD inhibitors and optimized the physicochemical conditions including pH, salt concentrations and detergent levels. Through an established AlphaScreen-based high-throughput screening assay against an in-house compound library, DCSM06 was identified as a novel SMARCA2-BRD inhibitor with an IC50 value of 39.9±3.0 μmol/L. Surface plasmon resonance demonstrated the binding between SMARCA2-BRD and DCSM06 (Kd=38.6 μmol/L). A similarity-based analog search led to identification of DCSM06-05 with an IC50 value of 9.0±1.4 μmol/L. Molecular docking was performed to predict the binding mode of DCSM06-05 and to decipher the structural basis of the infiuence of chemical modifications on inhibitor potency. DCSM06-05 may be used as a starting point for further medicinal chemistry optimization and could function as a chemical tool for SMARCA2-related functional studies.

21 citations


Journal ArticleDOI
TL;DR: DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention against cancer by blocking the leukemic xenograft growth in mice.

17 citations


Journal ArticleDOI
TL;DR: A fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors was developed and the minimal sequence requirement was determined by using this system.
Abstract: Aberrant activity of enhancer of zeste homolog 2 (EZH2) is associated with a wide range of human cancers. The interaction of EZH2 with embryonic ectoderm development (EED) is required for EZH2's catalytic activity. Inhibition of the EZH2-EED complex thus represents a novel strategy for interfering with the oncogenic potentials of EZH2 by targeting both its catalytic and non-catalytic functions. To date, there have been no reported high-throughput screening (HTS) assays for inhibitors acting at the EZH2-EED interface. In this study, we developed a fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors. The tracer peptide sequences, positions of fluorescein labeling, and a variety of physicochemical conditions were optimized. The high Z' factors (>0.9) at a variety of DMSO concentrations suggested that this system is robust and suitable for HTS. The minimal sequence requirement for the EZH2-EED interaction was determined by using this system. A pilot screening of an in-house compound library containing 1600 FDA-approved drugs identified four compounds (apomorphine hydrochloride, oxyphenbutazone, nifedipine and ergonovine maleate) as potential EZH2-EED interaction inhibitors.

16 citations


Journal ArticleDOI
TL;DR: A series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B.
Abstract: Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy. Their inhibitory effects on PTP1B and T-cell protein tyrosine phosphatase (TCPTP) were evaluated, and several compounds displayed significant inhibitory potency and specific selectivity over PTP1B. The structure–activity relationship (SAR) and molecular docking analyses are also described.

15 citations


Journal ArticleDOI
TL;DR: A HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor is developed, through which compound 3 and its analogues as potent DOT1l inhibitors with promising MLL-rearranged leukemia therapeutic application are discovered.

13 citations


Journal ArticleDOI
TL;DR: DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation, as well as the results showed that most of the compounds have strong anti DOT1L activities.

11 citations


ComponentDOI
TL;DR: 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer, and mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth.

Journal ArticleDOI
TL;DR: It is demonstrated that combination of berberine with OPCs could significantly improve the pharmacokinetics and hypoglycemic efficacy of BB, which is valuable for future exploration of the combination of BB and O PCs as oral hypogly diabetic agents.
Abstract: This study investigated the possible enhancement of berberine’s (BB) hypoglycemic activity by oligomeric proanthocyanidins (OPCs) and its underlying mechanism. The hypoglycemic activity of the studied compounds was evaluated in diabetic db/db mice. The cellular uptake and efflux of BB with or without OPCs were investigated using Caco-2 intestinal cells. A pharmacokinetic study of BB and OPCs was performed in Sprague Dawley (SD) mice by oral administration of the study compounds. Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was employed to determine the cellular efflux, retention, and the serum concentrations of the compounds. The results revealed that OPCs considerably potentiated the hypoglycemic efficacy of BB in diabetic db/db mice. In the in vitro experiments, OPCs significantly inhibited the efflux and increased the uptake of the P-glycoprotein (P-gp) substrate rhodamine-123 (R123) and BB in Caco-2 intestinal cells. Moreover, OPCs substantially reduced the expression of P-gp in Caco-2 cells. The inhibition of BB efflux by OPCs was translated into the improved pharmacokinetics in vivo. When co-administered, OPCs obviously increased the average maximum concentration of BB in mice. In summary, this study demonstrated that combination of BB with OPCs could significantly improve the pharmacokinetics and hypoglycemic efficacy of BB, which is valuable for future exploration of the combination of BB and OPCs as oral hypoglycemic agents.

Journal ArticleDOI
02 Nov 2018
TL;DR: It is suggested that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates.
Abstract: Small molecular inhibitors targeting BRD4 family proteins are emerging as promising therapies in many types of human malignancies. However, whether BRD4, as well as other BET family members, may serve as therapeutic targets in renal cell carcinoma (RCC) remains unknown. In this study, we found that both BRD2 and BRD4 were over-expressed in RCC tissues, knock-down both of which achieved potent anti-proliferative effects in RCC cells. A novel category of BET inhibitors, originated from an approved drug Nitroxoline, were synthesized and evaluated with biochemical and cellular assays, as well as the method of crystallography. The complex crystal structures of several compounds in this category with the first bromodomain of BRD4 (BRD4-BD1) were solved, revealing the binding mechanism and facilitating further structural optimizations. Among them, compound BDF-1253 showed an approximately four-fold improvement in BRD4 inhibition compared with the prototype Nitroxoline and had good selectivity for BET proteins against other bromodomain proteins or epi-enzymes in biochemical assays. Compound BDF-1253 efficiently suppressed the expression of BET downstream genes, impaired RCC cells viability via inducing cell cycle arrest and apoptosis, and decreased tumor growth in RCC xenografts. In summary, these results suggest that inhibition of BET family members has great therapeutic potentials in the treatment of RCC, and the novel series of BET inhibitors reported here are promising to become RCC drug candidates.

Journal ArticleDOI
TL;DR: To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5H-thieno[3',2':3,4]pyrido[2,1-a]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro.

Journal ArticleDOI
TL;DR: In this paper, the International Thermonuclear Experimental Reactor radial X-ray camera is designed to measure the poloidal profile of the plasma Xray emission with high spatial and temporal resolutions and will be installed inside equatorial port 12.
Abstract: International Thermonuclear Experimental Reactor radial X-ray camera is designed to measure the poloidal profile of the plasma X-ray emission with high spatial and temporal resolutions and will be installed inside equatorial port 12. Due to the harsh environment of neutron and gamma radiations, nuclear radiation hardness of many components has to be considered in design and test, including silicon detector array, electronics, and cabling. As for electronics put in a port cell, a preliminary design of highly integrated preamplifier and program controllable mid-amplifier has been completed, and many tests have been done to investigate the radiation hardness performance of the amplifiers together with detectors. In the Cf-252 neutron test with flux of $\sim 2.23\times 10^{3}\,\,\text {n}\cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ and fluence greater than $1.0\times 10^{10}\,\,\text {n}\cdot \text {cm}^{-2}$ , there was no performance degradation in detector and preamplifier. In the Co-60 gamma test with a dose rate of $0.5\,\,\text {Gy}\cdot \text {min}^{-1}$ and an accumulated dose of 200 Gy, the performance change was not found in preamplifier and mid-amplifier except for some radiation damage to the power module in the board of preamplifier. In the following accelerator neutron test where the neutron flux is $\sim 5\times 10^{7}\,\,\text {n}\cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ and neutron fluence is $2\times 10^{12}\,\,\text {n}\cdot \text {cm}^{-2}$ , the functional problem was not found in preamplifier and cable, while there were occurrences of single-event effect in mid-amplifier. The detector underwent 10% decrease of sensitivity to visible light. In addition, shielding cabinet was designed to provide good protection for electronics inside.

Posted ContentDOI
12 Oct 2018-bioRxiv
TL;DR: An automated machine learning approach is used to reveal slow conformational motions and thus distinct conformational states of SETD8, and the resulting models provide unprecedented mechanistic insight into how protein dynamics plays a role in SAM binding and thus catalysis.
Abstract: Elucidating conformational heterogeneity of proteins is essential for understanding protein functions and developing exogenous ligands for chemical perturbation. While structural biology methods can provide atomic details of static protein structures, these approaches cannot in general resolve less populated, functionally relevant conformations and uncover conformational kinetics. Here we demonstrate a new paradigm for illuminating dynamic conformational landscapes of target proteins. SETD8 (Pr-SET7/SET8/KMT5A) is a biologically relevant protein lysine methyltransferase for in vivo monomethylation of histone H4 lysine 20 and nonhistone targets. Utilizing covalent chemical inhibitors and depleting native ligands to trap hidden high-energy conformational states, we obtained diverse novel X-ray structures of SETD8. These structures were used to seed massively distributed molecular simulations that generated six milliseconds of trajectory data of SETD8 in the presence or absence of its cofactor. We used an automated machine learning approach to reveal slow conformational motions and thus distinct conformational states of SETD8, and validated the resulting dynamic conformational landscapes with multiple biophysical methods. The resulting models provide unprecedented mechanistic insight into how protein dynamics plays a role in SAM binding and thus catalysis, and how this function can be modulated by diverse cancer-associated mutants. These findings set up the foundation for revealing enzymatic mechanisms and developing inhibitors in the context of conformational landscapes of target proteins.

Journal ArticleDOI
TL;DR: In this article, the International Thermonuclear Experimental Reactor radial X-ray camera is designed to measure the poloidal profile of the plasma Xray emission with high spatial and temporal resolutions and will be installed inside equatorial port 12.
Abstract: International Thermonuclear Experimental Reactor radial X-ray camera is designed to measure the poloidal profile of the plasma X-ray emission with high spatial and temporal resolutions and will be installed inside equatorial port 12. Due to the harsh environment of neutron and gamma radiations, nuclear radiation hardness of many components has to be considered in design and test, including silicon detector array, electronics, and cabling. As for electronics put in a port cell, a preliminary design of highly integrated preamplifier and program controllable mid-amplifier has been completed, and many tests have been done to investigate the radiation hardness performance of the amplifiers together with detectors. In the Cf-252 neutron test with flux of $\sim 2.23\times 10^{3}\,\,\text {n}\cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ and fluence greater than $1.0\times 10^{10}\,\,\text {n}\cdot \text {cm}^{-2}$ , there was no performance degradation in detector and preamplifier. In the Co-60 gamma test with a dose rate of $0.5\,\,\text {Gy}\cdot \text {min}^{-1}$ and an accumulated dose of 200 Gy, the performance change was not found in preamplifier and mid-amplifier except for some radiation damage to the power module in the board of preamplifier. In the following accelerator neutron test where the neutron flux is $\sim 5\times 10^{7}\,\,\text {n}\cdot \text {cm}^{-2}\cdot \text {s}^{-1}$ and neutron fluence is $2\times 10^{12}\,\,\text {n}\cdot \text {cm}^{-2}$ , the functional problem was not found in preamplifier and cable, while there were occurrences of single-event effect in mid-amplifier. The detector underwent 10% decrease of sensitivity to visible light. In addition, shielding cabinet was designed to provide good protection for electronics inside.

Patent
05 Nov 2018
TL;DR: In this paper, the authors describe the properties of different types of methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]Pyrimidine-6-carboxylic acid maleate (CAR maleate)
Abstract: 본 발명은 (R)-메틸-2-(3-아미노피페리딘-1-일)-3-(2-시아노벤질)-4-카르보닐-3,4-디히드로티오펜[3,2-d]피리미딘-6-카르복실산말레산염((R)-Methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]Pyrimidine-6-carboxylic acid maleate)의 다결정형 및 이의 제조 방법에 관한 것으로, 상기 결정형은 고 안정성 및 저 흡습성의 결정체이고, 상기 결정형은 결정형 A, 결정형 B 및 결정형 C로부터 선택된다. 또한, 본 발명의 결정형은 비교적 강한 체내 당 강하 활성을 구비하고, II형 당뇨병 및/또는 II형 당뇨병의 합볍증을 치료 또는 예방하기 위한 신규한 약물의 제조에 사용될 수 있다.