12 results on '"Yang Lingling"'
Search Results
2. Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates
- Author
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Yang, Fan, Su, Huilin, Deng, Ji, Mou, Luohe, Wang, Huali, Li, Rong, Dai, Qing-Qing, Yan, Yu-Hang, Qian, Shan, Wang, Zhouyu, Li, Guo-Bo, and Yang, Lingling
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- 2021
- Full Text
- View/download PDF
3. Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors
- Author
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Yang, Lingling, Ma, Xiaobo, Yuan, Chen, He, Yanying, Li, Ling, Fang, Sha, Xia, Wei, He, Tao, Qian, Shan, Xu, Zhihong, Li, Guobo, and Wang, Zhouyu
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- 2017
- Full Text
- View/download PDF
4. Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
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Yang Lingling, Zhenling Wang, Ji Deng, Kai-Rong Zhu, Chao Li, Guo-Bo Li, Wenfang Li, Qing-Qing Dai, Yu-Hang Yan, and Wei Chen
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Carboxylic Acids ,Microbial Sensitivity Tests ,medicine.disease_cause ,Meropenem ,beta-Lactamases ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,polycyclic compounds ,medicine ,Escherichia coli ,Animals ,Humans ,Tissue Distribution ,Pharmacology ,Mice, Inbred ICR ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Pseudomonas aeruginosa ,Chemistry ,Organic Chemistry ,Imidazoles ,Active site ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,biology.organism_classification ,Anti-Bacterial Agents ,Rats ,Biochemistry ,biology.protein ,Female ,Antibacterial activity ,Bacterial outer membrane ,beta-Lactamase Inhibitors ,Bacteria ,medicine.drug - Abstract
Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed most potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
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- 2021
5. Discovery of new human Sirtuin 5 inhibitors by mimicking glutaryl-lysine substrates
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Guo-Bo Li, Hua-Li Wang, Fan Yang, Luohe Mou, Shan Qian, Ji Deng, Yu-Hang Yan, Rong Li, Yang Lingling, Qing-Qing Dai, Zhouyu Wang, and Huilin Su
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SIRT5 ,High selectivity ,Lysine ,Nicotinamide adenine dinucleotide ,Cofactor ,Substrate Specificity ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Humans ,Sirtuins ,Epigenetics ,Enzyme Inhibitors ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Thiourea ,General Medicine ,Metabolic pathway ,Biochemistry ,chemistry ,Sirtuin ,biology.protein ,Propionates - Abstract
Human sirtuin 5 (SIRT5) plays pivotal roles in metabolic pathways and other biological processes, and is involved in several human diseases including cancer. Development of new potent and selective SIRT5 inhibitors is currently desirable to provide potential therapeutics for related diseases. Herein, we report a series of new 3-thioureidopropanoic acid derivatives, which were designed to mimic the binding features of SIRT5 glutaryl-lysine substrates. Structure-activity relationship studies revealed several compounds with low micromolar inhibitory activities to SIRT5. Computational and biochemical studies indicated that these compounds exhibited competitive SIRT5 inhibition with respect to the glutaryl-lysine substrate rather than nicotinamide adenine dinucleotide cofactor. Moreover, they showed high selectivity for SIRT5 over SIRT1-3 and 6 and could stabilize SIRT5 proteins as revealed by thermal shift analyses. This work provides an effective substrate-mimicking strategy for future inhibitor design, and offers new inhibitors to investigate their therapeutic potentials in SIRT5-associated disease models.
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- 2021
6. Sensitive fluorogenic substrates for sirtuin deacylase inhibitor discovery
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Yubin Luo, Guo-Bo Li, Meng-Yi Huang, Sha Liu, Yu-Hang Yan, Yamei Yu, Yang Lingling, Hua-Li Wang, Xi Zheng, and Zhu-Jun Yu
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SIRT5 ,SIRT3 ,Peptide ,SIRT2 ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Discovery ,Humans ,Sirtuins ,Enzyme Inhibitors ,Fluorescent Dyes ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Active site ,Isothermal titration calorimetry ,General Medicine ,0104 chemical sciences ,Biochemistry ,Sirtuin ,biology.protein ,NAD+ kinase - Abstract
Sirtuins (SIRTs) are NAD+-dependent lysine deacylases, regulating many important biological processes such as metabolism and stress responses. SIRT inhibitors may provide potential benefits against SIRT-driven human diseases. Development of efficient assay platforms based on fluorogenic substrates will facilitate the discovery of high-quality SIRT inhibitors. We here report 16 new fluorogenic peptide substrates (P1-P16) designed with structurally diverse tetrapeptides and acyl modifications. Tests of P1-P16 against SIRT isoforms identified several sensitive substrates for SIRT1, SIRT2, SIRT3 and SIRT5, which manifested lower KM values and higher catalytic efficiency, and particularly had less signal interference in inhibitor screening compared with our previously reported internally quenched fluorescent substrates. Co-crystallization of sensitive substrates P13 and P15 with SIRT5 revealed an unexpected binding mode, involving interactions with residues from active site bordering surfaces, different from that observed for other peptides derived from natural protein substrates. By using SIRT5 sensitive substrates, we found that TW-37, a Bcl-2 inhibitor, displayed low micromolar inhibition to SIRT5, which was further validated by isothermal titration calorimetry analyses, offering a new point to develop dual-action SIRT5/Bcl-2 inhibitors against cancers. This work provides assay platform and structural basis for developing new substrates and inhibitors targeting human SIRTs.
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- 2020
7. X-ray crystal structure guided discovery of new selective, substrate-mimicking sirtuin 2 inhibitors that exhibit activities against non-small cell lung cancer cells
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Yuan Chen, Guo-Bo Li, Sha Liu, Yu-Hang Yan, Si-Yu Liu, Yamei Yu, Hua-Li Wang, Zhouyu Wang, Zhu-Jun Yu, Lei Zhong, Qiang Chen, Chengyong Wu, Yang Lingling, and Yuxi Wang
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0301 basic medicine ,Models, Molecular ,Lung Neoplasms ,Cell Survival ,Cell ,Antineoplastic Agents ,Nicotinamide adenine dinucleotide ,SIRT2 ,Crystallography, X-Ray ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Sirtuin 2 ,Carcinoma, Non-Small-Cell Lung ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Humans ,Cell Proliferation ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell growth ,Organic Chemistry ,Cancer ,General Medicine ,medicine.disease ,Cell biology ,Histone Deacetylase Inhibitors ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Acetylation ,030220 oncology & carcinogenesis ,Sirtuin ,biology.protein ,NAD+ kinase ,Drug Screening Assays, Antitumor - Abstract
Human sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacylase, and is implicated in human diseases including cancer. Selective small-molecule inhibitors for SIRT2 are sought as chemical tools and potential therapeutics. Here we report the X-ray crystal structure guided structure-activity relationship studies of new N-(3-(phenoxymethyl)phenyl)acetamide derivatives with SIRT2, which led to the identification of potent, selective SIRT2 inhibitors. Crystallographic analyses reveal that the new inhibitors act via inducing the formation of an enlarged hydrophobic pocket and particularly mimicking the interactions made by myristoylated-lysine substrates. The most potent inhibitor 24a could dose-dependently elevate the acetylation level of α-tubulin in the non-small cell lung cancer H441 cells, which have a high expression level of SIRT2 as determinated by Western blotting analyses. Further cellular assays reveal that 24a restrains cell growth mainly through inhibiting cellular proliferation rather than inducing apoptosis. Moreover, 24a could suppress the migration and invasion of H441 cells. These results provide an excellent basis for further development of new potent, selective, and cell active SIRT2 inhibitors as chemical tools and potential therapeutics for SIRT2-driven non-small cell lung cancers.
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- 2018
8. LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors
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Shengyong Yang, Guo-Bo Li, Sen Ji, Rong-Jie Zhang, Kai Chen, Yang Lingling, Shuang Ma, and Lei Zhong
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Models, Molecular ,Protein Conformation ,In silico ,Syk ,Cell Line ,Automation ,Lead (geology) ,Drug Discovery ,Humans ,Syk Kinase ,Computer Simulation ,Protein Kinase Inhibitors ,Pharmacology ,Binding Sites ,Ligand efficiency ,Chemistry ,Drug discovery ,Organic Chemistry ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Protein-Tyrosine Kinases ,Ligand (biochemistry) ,Vascular Endothelial Growth Factor Receptor-2 ,Combinatorial chemistry ,Drug Design ,Target protein ,Algorithms ,Function (biology) - Abstract
Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.
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- 2015
9. Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors
- Author
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Xu Zhihong, Ma Xiaobo, Yanying He, Fang Sha, Shan Qian, Li Ling, Yuan Chen, Wei Xia, Yang Lingling, Tao He, Guo-Bo Li, and Zhouyu Wang
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0301 basic medicine ,SIRT3 ,Thio ,Antineoplastic Agents ,Breast Neoplasms ,SIRT2 ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Sirtuin 2 ,Tubulin ,Acetamides ,Drug Discovery ,medicine ,Humans ,Breast ,Pharmacology ,biology ,Chemistry ,Organic Chemistry ,Autophagy ,Cancer ,General Medicine ,Cell cycle ,medicine.disease ,Histone Deacetylase Inhibitors ,Molecular Docking Simulation ,030104 developmental biology ,Pyrimidines ,Biochemistry ,Acetylation ,030220 oncology & carcinogenesis ,Sirtuin ,biology.protein ,MCF-7 Cells ,Female - Abstract
Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC50 value of 42 nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of α-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases.
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- 2016
10. Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization
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Heng-Xiu Yan, Jun Zou, Ze-Rong Wang, Shan Feng, Yang Lingling, Pan Ji, Guo-Bo Li, Qi-Zheng Sun, Shuang Ma, and Shengyong Yang
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Models, Molecular ,Pharmacology ,Virtual screening ,Dose-Response Relationship, Drug ,Molecular Structure ,Pyrimidine ,Casein Kinase I ,Stereochemistry ,Organic Chemistry ,General Medicine ,Hit to lead ,Diamines ,Combinatorial chemistry ,High-Throughput Screening Assays ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pyrimidines ,chemistry ,Diamine ,Drug Discovery ,Casein kinase 1 ,Pharmacophore ,Protein Kinase Inhibitors ,Lead compound - Abstract
Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM.
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- 2012
11. Synthesis and structure-activity relationship of non-phosphorus-based fructose-1,6-bisphosphatase inhibitors: 2,5-Diphenyl-1,3,4-oxadiazoles
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Jing-Ya Li, Jia Li, Yang Lingling, Chang Liang, Hai-Bing He, Benren Liao, Fan Yang, Jie Tang, and Li-Xin Gao
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Stereochemistry ,Protein Conformation ,In silico ,Kinetics ,Allosteric regulation ,Fructose 1,6-bisphosphatase ,chemistry.chemical_element ,Chemistry Techniques, Synthetic ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Enzyme Inhibitors ,Pharmacology ,chemistry.chemical_classification ,Oxadiazoles ,biology ,Chemistry ,Phosphorus ,Organic Chemistry ,General Medicine ,Fructose-Bisphosphatase ,Rats ,Molecular Docking Simulation ,Enzyme ,Glucose ,Gluconeogenesis ,Biochemistry ,biology.protein ,Hepatocytes - Abstract
With the aim of discovering a novel class of non-phosphorus-based fructose-1,6-bisphosphatase (FBPase) inhibitors, a series of 2,5-diphenyl-1,3,4-oxadiazoles were synthesized based on the hit compound (1) resulting from a high-throughput screening (HTS). Structure-activity relationship (SAR) studies led to the identification of several compounds with comparable inhibitory activities to AMP, the natural allosteric inhibitor of FBPase. Notably, compound 22 and 27b, bearing a terminal carboxyl or 1H-tetrazole, demonstrated remarkable inhibition to gluconeogenesis (GNG). In addition, both inhibition and binding mode to the enzyme were investigated by enzymatic kinetics and in silico experiments for representative compounds 16 and 22.
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- 2014
12. Combined SVM-based and docking-based virtual screening for retrieving novel inhibitors of c-Met
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Qi Huang, Xiaoyan Wang, Yang Lingling, Lei Di-wu, Yu-Lan Wang, You-Li Pan, Huan-Zhang Xie, Jian-Ping Zhou, Shengyong Yang, Lei Zhong, and Qing-Qing Xie
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Pharmacology ,Models, Molecular ,Virtual screening ,C-Met ,Chemistry ,Drug discovery ,Organic Chemistry ,Antineoplastic Agents ,General Medicine ,Proto-Oncogene Proteins c-met ,Combinatorial chemistry ,Support vector machine ,c-Met inhibitor ,Inhibitory potency ,chemistry.chemical_compound ,Docking (molecular) ,Drug Discovery ,PubChem - Abstract
Aberrant c-Met activation has been demonstrated to be implicated in tumorigenesis and anti-cancer drug resistance. Discovery of c-Met inhibitors has attracted much attention in recent years. In this study, a support vector machine (SVM) classification model that discriminates c-Met inhibitors and non-inhibitors was first developed. Evaluation through screening a test set indicates that combined SVM-based and docking-based virtual screening (SB/DB-VS) considerably increases hit rate and enrichment factor compared with the individual methods. Thus the combined SB/DB-VS approach was adopted to screen PubChem, Specs, and Enamine for c-Met inhibitors. 75 compounds were selected for in vitro assays. Eight compounds display a good inhibitory potency against c-Met. Five of them are found to have novel scaffolds, implying a good potential for further chemical modification.
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- 2011
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