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https://www.readbyqxmd.com/read/28806746/selective-small-chemical-inhibitors-of-protein-arginine-methyltransferase-5-with-anti-lung-cancer-activity
#1
Gui-Mei Kong, Min Yu, Zhongping Gu, Zhi Chen, Rui-Ming Xu, Deon O'Bryant, Zhengxin Wang
Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation...
2017: PloS One
https://www.readbyqxmd.com/read/28806600/design-synthesis-and-evaluation-of-newer-5-6-dihydropyrimidine-2-1h-thiones-as-gaba-at-inhibitors-for-anticonvulsant-potential
#2
Meeta Sahu, Nadeem Siddiqui, Ramsha Iqbal, Vidushi Sharma, Sharad Wakode
Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC50) of 18...
July 28, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28805446/epigallocatechin-gallate-as-an-anti-obesity-therapeutic-compound-an-in-silico-approach-for-structure-based-drug-designing
#3
Muhammad Shahid Javaid, Noreen Latief, Bushra Ijaz, Usman Ali Ashfaq
Epigallocatechin gallate is a polyphenol of tea plants. Other than tea its trace amounts are found in apple skin, onions and plums. It has anti-adipogenic and anti-oxidant potential. It was investigated that epigallocatechin gallate stopped the adipogenic differentiation of mice mesenchymal stem cells but its underlying mechanism is not well understood. Different proteins and transcription factors responsible for differentiation of adipocytes could be its targets. This study was designed to determine the potential target of epigallocatechin gallate in human...
August 14, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28805312/the-dock-and-coalesce-mechanism-for-the-association-of-a-wasp-disordered-region-with-the-cdc42-gtpase
#4
Li Ou, Megan Matthews, Xiaodong Pang, Huan-Xiang Zhou
Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and-coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites. Here, by a combination of experiment and computation, we determined the precise form of dock-and-coalesce operating in the association between the intrinsically disordered GTPase binding domain (GBD) of the Wiskott-Aldrich Syndrome protein (WASP) and the Cdc42 GTPase...
August 14, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28805269/cloning-and-bacterial-expression-systems-for-recombinant-human-heparanase-production-substrate-specificity-investigation-by-docking-of-a-putative-heparanase-substrate
#5
Angela Pennacchio, Alessandro Capo, Simonetta Caira, Annabella Tramice, Antonio Varriale, Maria Staiano, Sabato D'Auria
Human heparanase (HPSE) is an enzyme that degrades the extracellular matrix. It is implicated in a multiplicity of physiological and pathological processes encouraging angiogenesis and tumor metastasis. The protein is a heterodimer composed from a subunit of 8 kDa and a subunit of 50 kDa. The two protein subunits are non-covalently associated. The cloning and expression of the two protein subunits in Escherichia coli, and their subsequent purification to homogeneity under native conditions result in the production of an active heparanase enzyme...
August 14, 2017: Biotechnology and Applied Biochemistry
https://www.readbyqxmd.com/read/28805144/a-qm-protein-ligand-investigation-of-anti-psychotic-drugs-with-the-dopamine-d2-receptor-d2r
#6
Ramin Ekhteiari Salmas, Yusuf Serhat Is, Serdar Durdagi, Matthias Stein, Mine Yurtsever
The dopamine D2 Receptor (D2R) is a member of the G-Protein Coupled Receptor (GPCR) family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used anti-psychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone and quetiapine. Due to their significant side effects and nonselective profiles, the discovery of novel drugs has become a challenge for researchers working in this field...
August 14, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28804615/pharmacological-effects-of-a-synthetic-quinoline-a-hybrid-of-tomoxiprole-and-naproxen-against-acute-pain-and-inflammation-in-mice-a-behavioral-and-docking-study
#7
Hossein Hosseinzadeh, Fatemeh Mazaheri, Razieh Ghodsi
OBJECTIVES: In the present study, we investigated the potential anti-nociceptive activity and acute anti-inflammatory effect of a synthetic quinoline compound (2-(4-Methoxyphenyl)benzo[h]quinoline-4-carboxylic acid, QC), possessing structural elements of both naproxen and tomoxiprole drugs. MATERIALS AND METHODS: The anti-nociceptive activity of QC was evaluated using chemical- and thermal-induced nociception models and its acute anti-inflammatory effect was evaluated by xylene-induced ear edema test in mice...
April 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28804613/novel-derivatives-of-phthalimide-with-potent-anticonvulsant-activity-in-ptz-and-mes-seizure-models
#8
Asghar Davood, Maryam Iman, Hanieh Pouriaiee, Hamed Shafaroodi, Sepideh Akhbari, Leila Azimidoost, Erfan Imani, Somaieh Rahmatpour
OBJECTIVES: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. MATERIALS AND METHODS: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models...
April 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28803976/canavalia-bonariensis-lectin-molecular-bases-of-glycoconjugates-interaction-and-antiglioma-potential
#9
Benildo Sousa Cavada, Mayara Torquato Lima Silva, Vinicius Jose Silva Osterne, Vanir Reis Pinto-Junior, Ana Paula Machado do Nascimento, Ingrid Alessandra Victoria Wolin, Isabella Aparecida Heinrich, Clareane Avelino Simplicio Nobre, Cleane Gomes Moreira, Claudia Figueiredo Lossio, Cintia Renata Costa Rocha, Jorge Luiz Martins, Kyria Santiago Nascimento, Rodrigo Bainy Leal
CaBo is a mannose/glucose-specific lectin purified from seeds of Canavalia bonariensis. In the present work, we report the CaBo crystal structure determined to atomic resolution in the presence of X-man, a specific ligand. Similar to the structural characteristics of other legume lectins, CaBo presented the jellyroll motif, a metal binding site occupied by calcium and manganese ions close to the carbohydrate-recognition domain (CRD). In vitro test of CaBo cytotoxicity against glioma cells demonstrated its ability to decrease the cellular viability and migration by induction of autophagy and cell death...
August 10, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28803799/constructing-novel-dihydrofuran-and-dihydroisoxazole-analogues-of-isocombretastatin-4-as-tubulin-polymerization-inhibitors-through-3-2-reactions
#10
Ming-Yu Song, Chen-Yu Cao, Qiu-Rui He, Qing-Miao Dong, Ding Li, Jiang-Jiang Tang, Jin-Ming Gao
[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47μM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32µM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28803776/mechanism-of-enzyme-repair-by-the-aaa-chaperone-rubisco-activase
#11
Javaid Y Bhat, Goran Miličić, Gabriel Thieulin-Pardo, Andreas Bracher, Andrew Maxwell, Susanne Ciniawsky, Oliver Mueller-Cajar, John R Engen, F Ulrich Hartl, Petra Wendler, Manajit Hayer-Hartl
How AAA+ chaperones conformationally remodel specific target proteins in an ATP-dependent manner is not well understood. Here, we investigated the mechanism of the AAA+ protein Rubisco activase (Rca) in metabolic repair of the photosynthetic enzyme Rubisco, a complex of eight large (RbcL) and eight small (RbcS) subunits containing eight catalytic sites. Rubisco is prone to inhibition by tight-binding sugar phosphates, whose removal is catalyzed by Rca. We engineered a stable Rca hexamer ring and analyzed its functional interaction with Rubisco...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28803043/structure-based-development-of-novel-triazoles-and-related-thiazolotriazoles-as-anticancer-agents-and-cdc25a-b-phosphatase-inhibitors-synthesis-in%C3%A2-vitro-biological-evaluation-molecular-docking-and-in-silico-adme-t-studies
#12
Sherif A F Rostom, Mona H Badr, Heba A Abd El Razik, Hayam M A Ashour
Synthesis of twenty nine new 1,2,4-triazoles and some derived thiazolothiadiazoles (structurally-relevant to some reported triazoles with anticancer and/or Cdc25A/B inhibitory activities) is described in this study. The obtained NCI's in vitro antitumor data revealed that five analogs (12, 15, 18, 19 and 22) displayed considerable tumor percentage growth inhibitory activity (GI%), among which the analog 18 possessed a special antitumor potential and spectrum. Additionally, the same five analogs showed a marginal GI effect on the normal breast epithelial cell line MCF-10A indicating higher selectivity towards cancer cells...
July 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802844/structural-basis-for-cullins-and-ring-component-inhibition-targeting-e3-ubiquitin-pathway-conductors-for-cancer-therapeutics
#13
Shagufta Shafique, Waqar Ali, Sonia Kanwal, Sajid Rashid
Cullin (CUL)-RING E3 ubiquitin ligases (CRLs) are attractive therapeutic targets as they regulate diverse biological processes important for cancer cell survival by conferring substrate selectivity for ubiquitination and degradation. Given the complexity of CRL complexes, steps toward the structure-based design of small-molecule inhibitors to modulate their activity have remained elusive. In this study, we explored the structural assembly and interaction details of closely related CUL scaffolds (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7) with RBX1 to screen potent small molecules against CRLs...
August 9, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28802701/acyl-modification-and-binding-of-mitochondrial-acp-to-multiprotein-complexes
#14
Heike Angerer, Stefan Schönborn, Jan Gorka, Ute Bahr, Michael Karas, Ilka Wittig, Juliana Heidler, Jan Hoffmann, Nina Morgner, Volker Zickermann
The mitochondrial acyl carrier protein (ACPM/NDUFAB1) is a central element of the mitochondrial fatty acid synthesis type II machinery. Originally ACPM was detected as a subunit of respiratory complex I but the reason for the association with the large enzyme complex remained elusive. Complex I from the aerobic yeast Yarrowia lipolytica comprises two different ACPMs, ACPM1 and ACPM2. They are anchored to the protein complex by LYR (leucine-tyrosine-arginine) motif containing protein (LYRM) subunits LYRM3 (NDUFB9) and LYRM6 (NDUFA6)...
August 9, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28802482/recent-advances-on-cdk-inhibitors-an-insight-by-means-of-in-silico-methods
#15
REVIEW
Marco Tutone, Anna Maria Almerico
The cyclin dependent kinases (CDKs) are a small family of serine/threonine protein kinases that can act as a potential therapeutic target in several proliferative diseases, including cancer. This short review is a survey on the more recent research progresses in the field achieved by using in silico methods. All the "armamentarium" available to the medicinal chemists (docking protocols and molecular dynamics, fragment-based, de novo design, virtual screening, and QSAR) has been employed to the discovery of new, potent, and selective inhibitors of cyclin dependent kinases...
August 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802226/taraxerol-a-pentacyclic-triterpenoid-from-abroma-augusta-leaf-attenuates-diabetic-nephropathy-in-type-2-diabetic-rats
#16
Ritu Khanra, Niloy Bhattacharjee, Tarun K Dua, Ashis Nandy, Achintya Saha, Jatin Kalita, Prasenjit Manna, Saikat Dewanjee
Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats...
August 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28802212/pharmacophore-based-design-of-some-multi-targeted-compounds-targeted-against-pathways-of-diabetic-complications
#17
Navriti Chadha, Om Silakari
Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc...
July 21, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28802166/design-synthesis-and-%C3%AE-amylase-inhibitory-activity-of-novel-chromone-derivatives
#18
Parthiban Valentina, Kaliappan Ilango, Subhash Chander, Sankaranarayanan Murugesan
Quercetin is one of the naturally occurring polyphenol flavonoid predominantly known for antidiabetic activity. In the present study, by considering the structural requirements, twenty two novel chromone derivatives (5-26) as α-amylase inhibitor were designed and subsequently in silico evaluated for drug likeness behavior. Designed compounds were synthesized, characterized by spectral analysis and finally evaluated for the inhibition of α-amylase activity by in vitro assay. Tested compounds exhibited significant to weak activity with IC50 range of 12-125µM...
August 1, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28802152/comparison-and-analysis-of-the-structures-and-binding-modes-of-antifungal-se-and-cyp51-inhibitors
#19
Bin Sun, Wanxu Huang, Min Liu, Kang Lei
With the abuse of clinical broad-spectrum antimicrobial agents, immunosuppressive agents, chemotherapy drugs, the emergence of pathogenic fungi resistance is more and more frequent. However, there is still no effective treatment for the fungal resistance. Squalenee epoxidase (SE) and 14 α-demethylase (CYP51) are important antifungal drug targets. In order to achieve a deeper insight into the structural characteristics and the action modes of SE and CYP51inhibitors, the homology model of SE (Candida albicans) was constructed using monooxygenase of Pseudomonas aeruginosa as template, and the reliability of model was confirmed by Ramachandran plots and Verify 3D...
August 1, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28802124/design-synthesis-and-bioevaluation-of-antitubulin-agents-carrying-diaryl-5-5-fused-heterocycle-scaffold
#20
Qile Xu, Maolin Sun, Zhaoshi Bai, Yueting Wang, Yue Wu, Haiqiu Tian, Daiying Zuo, Qi Guan, Kai Bao, Yingliang Wu, Weige Zhang
A series of 3,6-diaryl-1H-pyrazolo[5,1-c][1,2,4]triazoles (I) and 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (II) as antitubulin agents were designed, synthesized and bioevaluated. Compounds (II) 4a, 4d, 4f, 4j, 4l and 4n showed potent antiproliferative activity at sub-micromolar or nanomolar concentrations against SGC-7901, A549 and HT-1080 cell lines, indicating that the bioisosteric replacement of the carbonyl group and B-ring of SMART and ABI with a 5,5-fused-heterocycle scaffold successfully maintained potent antiproliferative activity...
June 1, 2017: European Journal of Medicinal Chemistry
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