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Chemical Biology & Drug Design

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https://www.readbyqxmd.com/read/29052968/non-steroidal-estrogen-receptor-isoform-selective-biphenyls
#1
Seema Bhatnagar, Anjali Soni, Swati Kaushik, Megha Rikhi, T R Santhosh Kumar, B Jayaram
Estrogen receptor (ER) has been a therapeutic target to treat ER positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ERα and ERβ are two isoforms sharing 56% identity, and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform selective ligands...
October 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29052961/amphiphilic-small-peptides-for-delivery-of-plasmid-dnas-and-sirnas
#2
Eun-Kyoung Bang, Hanna Cho, Sean S-H Jeon, Na Ly Tran, Dong-Kwon Lim, Wooyoung Hur, Taebo Sim
Although various delivery systems for nucleic acids have been reported, development of an efficient and non-toxic delivery carrier is still a key subject for gene therapy. In order to find new efficient delivery carriers for nucleic acids, we synthesized amphiphilic peptides composed of a guanidino group, an oleyl group, and a cysteine. We prepared both linear and branched types of peptides, and found that the linear peptides were superior to the branched peptides as nucleic acid carriers. Our study also suggested that the intermolecular cysteine disulfides might allow the linear peptides to form the optimal particle sizes with nucleic acids for cellular uptake...
October 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29052959/peptide-ligands-for-targeting-the-extracellular-domain-of-egfr-comparison-between-linear-and-cyclic-peptides
#3
Tyrslai M Williams, Rushikesh Sable, Sitanshu Singh, M Graça H Vicente, Seetharama Jois
Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity towards EGFR...
October 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29052945/design-synthesis-and-cytotoxic-evaluation-of-novel-scopoletin-derivatives
#4
LETTER
Wei Shi, Jinlu Zhang, Na Bao, Fuqin Guan, Li Chen, Jianbo Sun
A series of scopoletin derivatives were designed and synthesized by introducing α-aminoacetamide, acrylamide and β-aminopropamide respectively to 3-position of scopoletin and their chemical structures were confirmed by ESI-MS, IR, (1) H NMR and (13) C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A549) by MTT method. Cytotoxic assay showed that compounds 7a, 7b, 7e, 7f, 8a and 8e exhibited more potent cytotoxicities compared to scopoletin...
October 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29045053/ensamble-based-adme-tox-profiling-and-virtual-screening-for-the-discovery-of-new-inhibitors-of-the-leishmania-mexicana-cysteine-protease-cpb2-8%C3%AE-cte
#5
Angela Scala, Antonio Rescifina, Nicola Micale, Anna Piperno, Tanja Schirmeister, Louis Maes, Giovanni Grassi
In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,β'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate to excellent activity (12-90% inhibition of the target enzyme at 20 μM). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-topology...
October 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29045039/design-of-potent-b-raf-v600e-inhibitors-by-mcss-strategy
#6
Ze-Feng Wang, Peng-Fei Wang, Jun-Ting Ma, Ying-Zi Chai, Hui-Min Hu, Wen-Long Gao, Zhong-Chang Wang, Bao-Zhong Wang, Hai-Liang Zhu
B-Raf kinase is a vital intermedium in the mitogen-activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases like somatic tumors. So far, the development of B-Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task...
October 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29044929/anticancer-activity-of-vmct1-analogs-against-mcf-7-cells
#7
Cibele Nicolaski Pedron, Gislaine Patricia Andrade, Roseli Hiromi Sato, Marcelo Der Torossian Torres, Giselle Cerchiaro, Anderson Orzari Ribeiro, Vani Xavier Oliveira Junior
Antimicrobial peptides are considered promising drug candidates due to their broad range of activity. VmCT1 (Phe-Leu-Gly-Ala-Leu-Trp-Asn-Val-Ala-Lys-Ser-Val-Phe-NH2 ) is an α-helical antimicrobial peptide that was obtained from the Vaejovis mexicanus smithi scorpion venom. Some of its analogs showed to be as antimicrobial as the wild type and they were designed for understanding the influence of physiochemical parameters on antimicrobial and hemolytic activity. Some cationic antimicrobial peptides exhibit anticancer activity so VmCT1 analogs were tested in order to verify the anticancer activity of this family of peptides...
October 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29034580/selective-inhibition-of-trpm2-channel-by-two-novel-synthesized-adpr-analogues
#8
Xiao Luo, Meng Li, Kaiyu Zhan, Wei Yang, Lihe Zhang, KeWei Wang, Peilin Yu, Liangren Zhang
Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5'-diphosphoribose (ADPR) analogues were synthesized and their activities and selectivity were evaluated. Whole-cell patch clamp recordings were employed for screen and evaluation of synthesized compounds...
October 15, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28994250/synthesis-and-evaluation-of-a-novel-99m-tc-nitrido-radiopharmaceutical-with-alendronate-dithiocarbamate-as-a-potential-bone-imaging-agent
#9
Xiaoqing Song, Yue Wang, Junbo Zhang, Zhonghui Jin, Weifang Zhang, Yanyan Zhang
Currently, a popular strategy for designing novel radioprobes as bone imaging agents is based on the concept of bifunctional radiopharmaceticals. Considering the dithiocarbamate ligand can act as a suitable bifunctional linking agent to attach technetium-99m ((99m) Tc) to corresponding target molecules, in this study, alendronate dithiocarbamate (ALNDTC) was synthesized and radiolabeled with [(99m) Tc≡N](2+) core by ligand-exchange reaction to produce (99m) TcN-ALNDTC complex, for the potential use as a novel probe for bone imaging...
October 10, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28994241/legumain-correlates-with-neuroblastoma-differentiation-and-can-be-used-in-prodrug-design
#10
Min Zhang, Zhiteng Jiang, Sheng Chen, Zhixiang Wu, Kai Chen, Yeming Wu
Neuroblastoma (NB) is a highly malignant solid tumor in children. The cysteine endopeptidase legumain is expressed in adult solid tumors, but its expression in NB has not been examined. In this study, we assayed legumain expression in two NB cell lines and in microarrays of tumor tissues collected from 46 children with undifferentiated NB, differentiated NB and ganglioneuroblastoma. Correlation analyses showed that legumain was expressed in all NB cell lines tested, and that expression correlated with the degree of tumor differentiation...
October 10, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28980439/peptide-bond-formations-through-flow-chemistry
#11
N Ahmed
Peptides and proteins play important roles in body functions(1) ,(2) and are used exclusively in drug discoveries, having advantages because of their high biological activity, high specificity, and low toxicity. For peptide synthesis, researchers mostly use the solid-phase peptide synthesis (SPPS)(3) with modern modifications.(4) However, scientists failed to overcome two main factors; the concentration and time required for peptide coupling. The flow-based technology may help in the rapid production of peptides due to having advantages over batch reactions(5-7) in terms of productivity, heat and mixing efficiency, safety, and reproducibility...
October 4, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28950055/design-synthesis-and-biological-evaluation-of-5-4-pyridin-4-yl-1h-1-2-3-triazol-1-yl-benzonitrile-derivatives-as-xanthine-oxidase-inhibitors
#12
Ting-Jian Zhang, Song-Ye Li, Yi Zhang, Qing-Xia Wu, Fan-Hao Meng
A series of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives (1a-p) was designed, synthesized and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 μM and 6.7 μM, respectively. The Lineweaver-Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor. SARs analysis revealed that a carbon atom occupying the X(3) position is not as effective as a nitrogen atom; and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency...
September 26, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28944571/ensemble-docking-to-difficult-targets-in-early-stage-drug-discovery-methodology-and-application-to-fibroblast-growth-factor-23
#13
Hector A Velazquez, Demian Riccardi, Zhousheng Xiao, L Darryl Quarles, C Ryan Yates, Jerome Baudry, Jeremy C Smith
Ensemble docking is now commonly used in early-stage in silico drug discovery, and can be used to attack difficult problems such as finding lead compounds which can disrupt protein:protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data(1) ...
September 25, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28944565/novel-tetrahydroacridine-derivatives-with-iodobenzoic-acid-moiety-as-multifunctional-acetylcholinesterase-inhibitors
#14
Robert Skibiński, Kamila Czarnecka, Małgorzata Girek, Ireneusz Bilichowski, Nina Chufarova, Elżbieta Mikiciuk-Olasik, Paweł Szymański
New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity towards cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases - acetylcholinesterase and butyrylcholinesterase, delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors towards AChE and BuChE than N-ethyl and N-propyl moieties compounds...
September 25, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28941159/molecular-modeling-studies-of-pseudouridine-isoxazolidinyl-nucleoside-analogues-as-potential-inhibitors-of-the-pseudouridine-5-monophosphate-glycosidase
#15
Giuseppe Floresta, Venerando Pistarà, Emanuele Amata, Maria Dichiara, Arcangelo Damigella, Agostino Marrazzo, Orazio Prezzavento, Francesco Punzo, Antonio Rescifina
In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5'-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5'-monophosphate glycosidase, leading to the enzyme inhibition...
September 22, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28941044/potential-biological-targets-for-bioassay-development-in-drug-discovery-of-sturge-weber-syndrome
#16
REVIEW
Fatemeh Mohammadipanah, Fatemeh Salimi
Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis...
September 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28905525/new-insights-into-the-mechanism-of-action-of-pyrazolo-1-2-a-benzo-1-2-3-4-tetrazin-3-one-derivatives-endowed-with-anticancer-potential
#17
Antonino Lauria, Francesco Mingoia, Aída Nelly García-Argáez, Riccardo Delisi, Annamaria Martorana, Lisa Dalla Via
Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect)...
September 14, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28901664/pharmacophore-based-virtual-screening-molecular-docking-molecular-dynamics-simulation-and-biological-evaluation-for-the-discovery-of-novel-brd4-inhibitors
#18
Guoyi Yan, Manzhou Hou, Jiang Luo, Chunlan Pu, Xueyan Hou, Suke Lan, Rui Li
Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests...
September 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28891599/expression-in-escherichia-coli-of-fusion-protein-comprising-%C3%AE-conotoxin-txib-and-preservation-of-selectivity-to-nicotinic-acetylcholine-receptors-in-the-purified-product
#19
Jinpeng Yu, Xiaopeng Zhu, Yang Yang, Sulan Luo, Dongting Zhangsun
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, which are widely distributed in the central and peripheral nervous system. The α6β2* nAChR is an important subtype, which is closely associated with nicotine addiction and movement disorders etc. α-conotoxin TxIB with 16-amino acid residues specifically targets α6β2* nAChR with no obvious effect on other nAChR subtypes. However, chemical synthesis of TxIB is expensive, and the quantity of native TxIB extracted from cone snail is limited...
September 11, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28886237/synthesis-quality-control-and-bio-evaluation-of-99m-tc-cyclophosphamide
#20
Tanveer Hussain Bokhari, Samina Roohi, Saira Hina, Muhammad Usman Akbar, Muhammad Sohaib, Munawar Iqbal
Cancer is found to be the leading cause of death worldwide characterized by uncontrolled cell division. Nuclear medicines imaging by using radiopharmaceuticals have pronounced potential for the diagnosis and treatment of cancers. Cyclophosphamide (CPH) is an antineoplastic drug which targets selectively cancer cells. In the present work, labelling of CPH with Tc-99m is performed for diagnostic purpose, which gave labelling yield as high as 99% by using 20μg SnCl2 .2H2 O, 200μg of ligand at pH 7 for 10 min reaction time at room temperature...
September 8, 2017: Chemical Biology & Drug Design
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