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Chemical Biology & Drug Design

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https://www.readbyqxmd.com/read/28816417/docking-field-based-qsar-and-pharmacophore-studies-on-the-substituted-pyrimidine-derivatives-targeting-hiv-1-reverse-transcriptase
#1
Ningning Fan, Shuang Zhang, Tao Sheng, Liang Zhao, Zhenming Liu, Junyi Liu, Xiaowei Wang
HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for anti-retroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of 0.8078, cross-validated value of 0...
August 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28816025/aromatic-interactions-at-the-ligand-protein-interface-implications-for-the-development-of-docking-scoring-functions
#2
Michal Brylinski
The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand-protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings...
August 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28815968/discovery-of-naphthyl-n-acylhydrazone-p38%C3%AE-mapk-inhibitors-with-in-vivo-anti-inflammatory-and-anti-tnf-%C3%AE-activity
#3
Rosana H C N Freitas, Natália M Cordeiro, Patrícia R Carvalho, Marina A Alves, Isabella A Guedes, Tayna S Valerio, Laurent E Dardenne, Lídia M Lima, Eliezer J Barreiro, Patrícia D Fernandes, Carlos A M Fraga
Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors, meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK) are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models...
August 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28816016/the-discovery-of-new-and-more-potent-chloropyramine-c4-analogues-for-the-potential-treatment-of-invasive-breast-cancer
#4
Sahar Kandil, Filippo Prencipe, Samuel Jones, Stephen Hiscox, Andrew D Westwell
Breast cancer (BC) is the second most common cancer worldwide, accounting for 25% of all female cancers. Although the survival rate has increased significantly in the past few decades, patients who develop secondary site metastasis as well as those diagnosed with triple negative breast cancer (TNBC) still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK-VEGFR3 signaling. More recently, C4 is reported to have SASH1 inducing properties. However, C4 exerts its antitumour and antiangiogenic effects at high micromolar concentrations (>100 μM) that would not be compatible with further drug development against invasive breast cancer driven by FAK signaling...
August 16, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28816013/new-neurotensin-analogue-radiolabeled-by-99m-technetium-as-a-potential-agent-for-tumor-identification
#5
Iman Emrarian, Nourollah Sadeghzadeh, Seyed Mohammad Abedi, Saeid Abediankenari
INTRODUCTION: It has been shown that more than 75% of ductal pancreatic adenocarcinomas are overexpress neurotensin (NT) receptors. Overexpression of NT receptors has been reported in various human tumor types. Hence, a non-invasive diagnosis and staging method could be very beneficial. In this work, we describe radiolabeling and evaluation of new neurotensin analogues to target neurotensin receptor-positive tumors such as pancreatic carcinoma. METHODS: Radiolabeling was performed at 95°C for 10 min using(99m) Tc in the presence of tricine/EDDA exchange labeling...
August 16, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28815904/comparative-in-vitro-study-on-cytotoxicity-of-recombinant-%C3%AE-hairpin-peptides
#6
Denis V Kuzmin, Anna A Emelianova, Mariana B Kalashnikova, Pavel V Panteleev, Sergey V Balandin, Ekaterina O Serebrovskaya, Oksana Yu Belogurova-Ovchinnikova, Tatiana V Ovchinnikova
Natural antimicrobial peptides (AMPs) are important components of the innate immune system with a wide spectrum of biological activity. In this study, we investigated the cytotoxic effect of three recombinant β-hairpin cationic AMPs: arenicin-1 from the polychaeta Arenicola marina, tachyplesin I from the horseshoe crab Tachypleus tridentatus, and gomesin from the spider Acanthoscurria gomesiana. All the three β-hairpin AMPs were overexpressed in E. coli. Different cell lines were incubated with various concentrations of the investigated AMPs in order to evaluate their cytotoxic activity...
August 16, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28791774/n-substituted-hydroxynapthalene-imino-oxindole-derivatives-as-new-class-of-pi3-kinase-inhibitor-and-breast-cancer-drug-molecular-validation-and-structure-activity-relationship-studies
#7
M Rajesh Kumar, Manikandan Alagumuthu, V Violet Dhayabaran
N-substituted hydroxynapthalene imino-oxindole derivatives (5a-g) were emerged as the inhibitors of the phosphoinositide 3-kinase (PI3K) which is a crucial regulator of apoptosis or programmed cell death. Electron donor/acceptor substituted indole-imine (5a-g) were achieved and the structures were elucidated by FTIR, 1H NMR, 13C NMR, and HRMS. PI3Ks inhibition potency was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF-7) cell lines was evaluated. In both activities, compounds 5c, 5d, 5f and were showed most potent activities...
August 9, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28791767/the-delivery-of-doxorubicin-of-multifunctional-%C3%AE-cyclodextrin-modified-cdse-zns-quantum-dots-for-bioactivity-and-nano-probing
#8
Mei-Xia Zhao, Bing-Jie Zhu, Wen-Jing Yao, Di-Feng Chen, Chaojie Wang
The modified quantum dots (QDs), have been used in intracellular probing and drug delivery because of their special chemical and physical properties. In this paper, two β-cyclodextrin (β-CD)-modified CdSe/ZnS QDs with strong optical emission properties were synthesized as drug carriers to induce apoptosis. The positively charged L-Arginine (L-Arg) and neutral L-Tryptophan (L-Trp) were selected as ligands to compare the effect of charge on bioactivity of QDs nanoparticles. The in vitro assays revealed that these modified QDs showed good Dox carrier ability and significantly high inhibition rate to cancer cells...
August 9, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28782285/metformin-enhances-doxorubicin-sensitivity-via-inhibition-of-doxorubicin-efflux-in-p-gp-overexpressing-mcf-7-cells
#9
Vahid Shafiei-Irannejad, Nasser Samadi, Bahman Yousefi, Roya Salehi, Kobra Velaei, Nosratollah Zarghami
Resistance against chemotherapy is still a major problem in successful cancer treatment in the clinic. Therefore, identifying new compounds with lower side effects and higher efficacy is an important approach to overcome multidrug resistance (MDR). Here, we investigated the activity and possible mechanism of the antidiabetic drug, metformin, in human doxorubicin (DOX) resistant breast cancer (MCF-7/DOX) cells. The effect of metformin on the cytotoxicity of DOX was evaluated by MTT assay. The P-gp mRNA/protein expression levels following treatment with metformin was determined using real time polymerase chain reaction (RT-PCR) and western blot analysis, respectively...
August 6, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28756638/structure-based-discovery-of-new-selective-small-molecule-sirtuin-5-inhibitors
#10
Sha Liu, Sen Ji, Zhu-Jun Yu, Hua-Li Wang, Xu Cheng, Wei-Jian Li, Li Jing, Yamei Yu, Qiang Chen, Ling-Ling Yang, Guo-Bo Li, Yong Wu
Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses, and is implicated in metabolism-related diseases. Small molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, 6 compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of new synthesized (E)-2-cyano-N-phenyl-3-(5-phenylfuran-2-yl)acrylamide derivatives/analogues were carried out structure-activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5...
July 30, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28741789/screening-of-curcumin-derived-isoxazole-pyrazoles-and-pyrimidines-for-their-anti-inflammatory-antinociceptive-and-cyclooxygenase-2-inhibition
#11
LETTER
Mahmood Ahmed, Muhammad Abdul Qadir, Abdul Hameed, Muhammad Imran, Muhammad Muddassar
Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In present study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles and pyrimidines then the synthesized molecules were evaluated for their anti-inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration...
July 25, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28734085/novel-menadione-hybrids-synthesis-anticancer-activity-and-cell-based-studies
#12
Chakka Vara Prasad, Vadithe Lakshma Nayak, Sistla Ramakrishna, Uppuluri Venkata Mallavadhani
A series of novel menadione based triazole hybrids were designed and synthesized by employing copper catalyzed azide-alkyne cycloaddition (CuAAC). All the synthesized hybrids were characterized by their spectral data ((1) H NMR, (13) C NMR, IR and HRMS). The synthesized compounds were evaluated for their anticancer activity against five selected cancer cell lines including lung (A549), prostate (DU-145), cervical (Hela), breast (MCF-7) and mouse melanoma (B-16) by using MTT assay. The screening results showed that majority of the synthesized compounds displayed significant anticancer activity...
July 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28734062/coumarins-and-adenosine-receptors-new-perceptions-in-structure-affinity-relationships
#13
André Fonseca, Maria João Matos, Santiago Vilar, Sonja Kachler, Karl-Norbert Klotz, Eugenio Uriarte, Fernanda Borges
Adenosine receptors (ARs) subtypes are involved in several physiological and pharmacological processes. Ligands able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective ARs ligands based on coumarin scaffold. Therefore, a series 3-phenylcarboxamidocoumarins were synthesised and their affinity for the human ARs subtypes was screened by radioligand binding assays for A1 , A2A and A3 receptors and for A2B by adenylyl cyclase assay...
July 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28734058/evaluation-of-2-benzylidene-1-tetralone-derivatives-as-antagonists-of-a1-and-a2a-adenosine-receptors
#14
Lesetja J Legoabe, Mietha M Van der Walt, Gisella Terre'Blanche
Antagonists of the adenosine receptors (A1 and A2A ) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2-benzylidene-1-tetralone derivatives as antagonists of A1 and/or A2A adenosine receptors. In general, the test compounds were found to be selective for the A1 adenosine receptor, with only three test compounds possessing affinity for both the A1 and A2A adenosine receptor. The 2-benzylidene-1-tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favorable adenosine A1 receptor binding, while C5 hydroxy substitution led to favorable A2A adenosine receptor affinity...
July 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28719094/discovery-and-characterization-of-a-novel-tryptophan-hydroxylase-1-inhibitor-as-a-prodrug
#15
Hailong Shi, Yaya Cui, Yifei Qin
Serotonin (5-HT) is an important neurotransmitter and paracrine signaling molecule in the gastrointestinal tract. Two distinct tryptophan hydroxylases (TPH), TPH1 and TPH2 are the rate-limiting enzymes in the 5-HT biosynthesis process. TPH1 expression is mainly limited in the enterochromaffin cells and distributed in peripheries such as the skin and gut, while TPH2 is the predominant isoform in the CNS. In this study, mol002291 was screened as a drug-like compound from the TCM database for the inhibitor of TPH...
July 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28719017/contrasting-sirtuin-and-parp-activity-of-selected-2-4-6-trisubstituted-benzimidazoles
#16
Keng Yoon Yeong, Soo Choon Tan, Chun-Wai Mai, Chee-Onn Leong, Felicia Fei-Lei Chung, Yean Kee Lee, Chin Fei Chee, Noorsaadah Abdul Rahman
Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activity. We showed that modification on benzimidazoles may alter their selectivity towards sirtuin or PARP-1 enzymes...
July 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28696589/in-vitro-activity-of-the-interaction-between-taxifolin-dihydroquercetin-and-pyrimethamine-against-toxoplasma-gondii
#17
Daniel A Abugri, William H Witola, Albert E Russell, Roberta M Troy
Toxoplasmosis is one of the most neglected zoonotic foodborne parasitic diseases that cause public health and socio-economic concern worldwide. The current drugs used for the treatment of toxoplasmosis have been identified to have clinical limitations. Hence, new drugs are urgently needed to eradicate T.gondii infections globally. Here, an in vitro anti-Toxoplasma gondii activity of taxifolin (dihydroquercetin) and dihydrofolate inhibitor (pyrimethamine) alone and in combination with a fixed concentration of pyrimethamine were investigated against the rapidly proliferating T...
July 11, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28675787/novel-pyrrolocycloalkylpyrazole-analogues-as-cb1-ligands
#18
Battistina Asproni, Ilaria Manca, Giansalvo Pinna, Elena Cichero, Paola Fossa, Gabriele Murineddu, Paolo Lazzari, Giovanni Loriga, Gérard A Pinna
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide based compounds were designed and synthesized for cannabinoid CB1 and CB2 receptor interaction. Any of the new synthesized compounds showed high affinity for CB2 receptor with Ki values superior to 314 nM, whereas some of them showed moderate affinity for CB1 receptor with Ki values inferior to 400 nM. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB1 receptor (Ki CB1 = 81 nM) and the highest CB2 /CB1 selectively ratio (>12)...
July 4, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28667699/influence-of-egcg-on-%C3%AE-synuclein-%C3%AE-s-aggregation-and-identification-of-their-possible-binding-mode-a-computational-study-by-using-molecular-dynamics-simulation
#19
Xuewei Liu, Shuangyan Zhou, Danfeng Shi, Qifeng Bai, Huanxiang Liu, Xiaojun Yao
The accumulation of intrinsically disordered α-synuclein (αS) protein that can form β-sheet-rich fibrils is linked to Parkinson diseases (PD). (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant active component in green tea and can inhibit the fibrillation of αS. The elucidation of this molecular mechanism will be helpful to understand the inhibition mechanism of EGCG to the fibrillation of αS and also to find more potential small molecules that can inhibit the aggregation of αS. In this work, in order to study the influence of EGCG on the structure of β-sheet-rich fibrils of α-synuclein (αS) and identification of their possible binding mode, molecular dynamics simulations of pentamer and decamer aggregates of αS in complex with EGCG were performed...
July 1, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28667670/preparation-characterization-and-in-vitro-evaluation-of-isoniazid-and-rifampicin-loaded-archaeosomes
#20
Azade Attar, Ceren Bakir, Basak Yuce-Dursun, Serap Demir, Emrah Cakmakci, Ozkan Danis, Meral Birbir, Ayse Ogan
The ability of Archaea to adapt their membrane lipid compositions to extreme environments has brought in archaeosomes into consideration for the development of drug delivery systems overcoming the physical, biological blockades that the body exhibits against drug therapies. In this study, we prepared unilamellar archaeosomes, from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and explored its potential as a drug delivery vehicle. Rifampicin and isoniazid which are conventional drugs in tuberculosis medication were loaded separately and together in the same archaeosome formulation for the benefits of the combined therapy...
July 1, 2017: Chemical Biology & Drug Design
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