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https://www.readbyqxmd.com/read/27921184/chemotherapeutic-drug-selectivity-between-wild-type-and-mutant-braf-kinases-in-colon-cancer
#1
Jianchun Zhang, Tao Ji
Oncogenic BRaf V600E mutation is involved in the development, invasion and metastasis of colon cancer. Selective inhibition of BRaf(V600E) mutant has been recognized as a therapeutic strategy for the cancer. Here, we carried out atomistic molecular dynamics (MD) simulations to characterize the structural basis, energetic property, and dynamics behavior of conformational change in BRaf activation loop upon the mutation. It is found that V600E mutation destabilizes inactive DFG-out conformation of activation loop and promotes its conversion to the active DFG-in conformation, thus conferring constitutive activity for BRaf kinase...
January 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/27920890/mesoporous-silica-nanoparticles-equipped-with-surface-nanovalves-for-ph-controlled-liberation-of-doxorubicin
#2
N V Roik, L A Belyakova
Silica carriers equipped with molecular and supramolecular pH-sensitive nanovalves were designed by combination of sol-gel synthesis and selective postsynthetic modification. Mesoporous structure of synthesized materials was characterized by low-temperature nitrogen adsorption-desorption, small-angle X-ray diffraction and transmission electron microscopy. Chemical immobilization of N-[N'-(N'-phenyl)-2-aminophenyl]aminoalkyl groups was confirmed by IR spectral and chemical analyses of surface layer. Loading and release behaviour of synthesized drug carriers was studied in phosphate buffer solutions with pH 5...
December 6, 2016: Interface Focus
https://www.readbyqxmd.com/read/27920719/bile-acids-in-neurodegenerative-disorders
#3
REVIEW
Hayley D Ackerman, Glenn S Gerhard
Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system...
2016: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/27920426/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#4
Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors...
December 2016: Scientific Reports
https://www.readbyqxmd.com/read/27919658/quinolizinium-as-a-new-fluorescent-lysosomotropic-probe
#5
Emmanouil Zacharioudakis, Tatiana Cañeque, Raúl Custodio, Sebastian Müller, Ana M Cuadro, Juan J Vaquero, Raphaël Rodriguez
We have synthesized a collection of quinolizinium fluorescent dyes for the purpose of cell imaging. Preliminary biological studies in human U2OS osteosarcoma cancer cells have shown that different functional groups appended to the cationic quinolizinium scaffold efficiently modulate photophysical properties but also cellular distribution. While quinolizinium probes are known nuclear staining reagents, we have identified a particular quinolizinium derivative salt that targets the lysosomal compartment. This finding raises the question of predictability of specific organelle targeting from structural features of small molecules...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27919612/an-in-tether-sulfoxide-chiral-center-influences-the-biophysical-properties-of-the-n-capped-peptides
#6
Jingxu Li, Yuan Tian, Dongyuan Wang, Yujie Wu, Xiyang Ye, Zigang Li
Thanks to their large binding interfaces, peptides are attractive ligands targeting protein-protein interactions compared with small molecules. Various strategies to improve peptides' pharmaceutical properties have been developed to constrain peptides into their functional three-dimensional structures. In our previous work, we reported that an in-tether chiral center could modulate peptides' biophysical properties. Herein, we applied this concept to construct a chiral sulfoxide center into the N-terminal end-cap system...
November 25, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27919066/designed-proteins-induce-the-formation-of-nanocage-containing-extracellular-vesicles
#7
Jörg Votteler, Cassandra Ogohara, Sue Yi, Yang Hsia, Una Nattermann, David M Belnap, Neil P King, Wesley I Sundquist
Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing self-assembling structures consisting of either nucleic acids or proteins, but strategies for engineering hybrid biological materials are only beginning to emerge. Here we describe the design of self-assembling protein nanocages that direct their own release from human cells inside small vesicles in a manner that resembles some viruses...
November 30, 2016: Nature
https://www.readbyqxmd.com/read/27918638/small-molecule-microarray-based-discovery-of-parp14-inhibitors
#8
Bo Peng, Ann-Gerd Thorsell, Tobias Karlberg, Herwig Schüler, Shao Q Yao
Poly(ADP-ribose) polymerases (PARPs) are key enzymes in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, and suffer from poor selectivity. PARP14 has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Herein, we describe a small molecule microarray-based strategy for high-throughput synthesis, screening of >1000 potential bidentate inhibitors of PARPs, and the successful discovery of a potent PARP14 inhibitor H10 with >20-fold selectivity over PARP1...
December 5, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27918208/investigational-hemagglutinin-targeted-influenza-virus-inhibitors
#9
Li-Yan Zeng, Jie Yang, Shuwen Liu
Seasonal influenza and pandemic outbreaks typically result in high mortality and morbidity associated with severe economic burdens. Vaccines and anti-influenza drugs have made great contributions to control the infection. However, antigenic drifts and shifts allow influenza viruses to easily escape immune neutralization and antiviral drug activity. Hemagglutinin (HA)is an important envelope protein for the entry of influenza viruses into host cells, thus, HA-targeted agents may be potential anti-influenza drugs...
December 5, 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27918135/star-polymocs-with-diverse-structures-dynamics-and-functions-by-three-component-assembly
#10
Yufeng Wang, Yuwei Gu, Eric G Keeler, Jiwon V Park, Robert G Griffin, Jeremiah A Johnson
We report star polymer metal-organic cage (polyMOC) materials whose structures, mechanical properties, functionalities, and dynamics can all be precisely tailored through a simple three-component assembly strategy. The star polyMOC network is composed of tetra-arm star polymers functionalized with ligands on the chain ends, small molecule ligands, and palladium ions; polyMOCs are formed via metal-ligand coordination and thermal annealing. The ratio of small molecule ligands to polymer-bound ligands determines the connectivity of the MOC junctions and the network structure...
December 5, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27917861/submillimetre-network-formation-by-light-induced-hybridization-of-zeptomole-level-dna
#11
Takuya Iida, Yushi Nishimura, Mamoru Tamura, Keisuke Nishida, Syoji Ito, Shiho Tokonami
Macroscopic unique self-assembled structures are produced via double-stranded DNA formation (hybridization) as a specific binding essential in biological systems. However, a large amount of complementary DNA molecules are usually required to form an optically observable structure via natural hybridization, and the detection of small amounts of DNA less than femtomole requires complex and time-consuming procedures. Here, we demonstrate the laser-induced acceleration of hybridization between zeptomole-level DNA and DNA-modified nanoparticles (NPs), resulting in the assembly of a submillimetre network-like structure at the desired position with a dramatic spectral modulation within several minutes...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27917399/retinoids-and-retinal-diseases
#12
Philip D Kiser, Krzysztof Palczewski
Recent progress in molecular understanding of the retinoid cycle in mammalian retina stems from painstaking biochemical reconstitution studies supported by natural or engineered animal models with known genetic lesions and studies of humans with specific genetic blinding diseases. Structural and membrane biology have been used to detect critical retinal enzymes and proteins and their substrates and ligands, placing them in a cellular context. These studies have been supplemented by analytical chemistry methods that have identified small molecules by their spectral characteristics, often in conjunction with the evaluation of models of animal retinal disease...
October 2016: Annual Review of Vision Science
https://www.readbyqxmd.com/read/27916965/pathway-analysis-and-metabolites-identification-by-metabolomics-of-etiolation-substrate-from-fresh-cut-chinese-water-chestnut-eleocharis-tuberosa
#13
Yi-Xiao Li, Yong-Gui Pan, Feng-Ping He, Meng-Qi Yuan, Shang-Bin Li
Fresh-cut Chinese water chestnuts (CWC) turn yellow after being peeled, reducing their shelf life and commercial value. Metabolomics, the systematic study of the full complement of small molecular metabolites, was useful for clarifying the mechanism of fresh-cut CWC etiolation and developing methods to inhibit yellowing. In this study, metabolic alterations associated with etiolation at different growth stages (0 day, 2 days, 3 days, 4 days, 5 days) from fresh-cut CWC were investigated using LC-MS and analyzed by pattern recognition methods (principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and orthogonal projection to latent structures-discriminant analysis (OPLS-DA))...
December 1, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27916946/natural-non-mulberry-silk-nanoparticles-for-potential-controlled-drug-release
#14
Juan Wang, Zhuping Yin, Xiang Xue, Subhas C Kundu, Xiumei Mo, Shenzhou Lu
Natural silk protein nanoparticles are a promising biomaterial for drug delivery due to their pleiotropic properties, including biocompatibility, high bioavailability, and biodegradability. Chinese oak tasar Antheraea pernyi silk fibroin (ApF) nanoparticles are easily obtained using cations as reagents under mild conditions. The mild conditions are potentially advantageous for the encapsulation of sensitive drugs and therapeutic molecules. In the present study, silk fibroin protein nanoparticles are loaded with differently-charged small-molecule drugs, such as doxorubicin hydrochloride, ibuprofen, and ibuprofen-Na, by simple absorption based on electrostatic interactions...
December 1, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27915293/molecular-mechanism-of-divalent-metal-induced-activation-of-ns3-helicase-and-insights-into-zika-virus-inhibitor-design
#15
Xiaocong Cao, Yajuan Li, Xiangyu Jin, Yuelong Li, Feng Guo, Tengchuan Jin
Zika virus has attracted increasing attention because of its potential for causing human neural disorders, including microcephaly in infants and Guillain-Barré syndrome. Its NS3 helicase domain plays critical roles in NTP-dependent RNA unwinding and translocation during viral replication. Our structural analysis revealed a pre-activation state of NS3 helicase in complex with GTPγS, in which the triphosphate adopts a compact conformation in the absence of any divalent metal ions. In contrast, in the presence of a divalent cation, GTPγS adopts an extended conformation, and the Walker A motif undergoes substantial conformational changes...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27915171/progress-in-the-development-of-%C3%AE-lactams-as-n-acylethanolamine-acid-amidase-naaa-inhibitors-synthesis-and-sar-study-of-new-potent-n-o-substituted-derivatives
#16
R Petracca, S Ponzano, S M Bertozzi, O Sasso, D Piomelli, T Bandiera, F Bertozzi
The anti-inflammatory effects resulting from raising the levels of palmitoylethanolamide (PEA), an endogenous bioactive lipid, led to envisage N-Acylethanolamine Acid Amidase (NAAA), the cysteine hydrolase mainly responsible for PEA degradation, as an attractive target for small molecule inhibitors. Previous work in our group identified serine-derived β-lactams as potent and systemically active inhibitors of NAAA activity. Aiming to expand the SAR study around this class of compounds, we investigated the effect of the substitution on the endocyclic nitrogen by designing and synthesizing a series of N-substituted β-lactams...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914949/anion-inhibition-profiles-of-the-%C3%AE-carbonic-anhydrase-from-the-pathogenic-bacterium-burkholderia-pseudomallei-responsible-of-melioidosis-and-highly-drug-resistant-to-common-antibiotics
#17
Sonia Del Prete, Daniela Vullo, Pietro Di Fonzo, Sameh M Osman, Zeid AlOthman, Claudiu T Supuran, Clemente Capasso
Burkholderia pseudomallei is a Gram-negative saprophytic bacterium responsible of melioidosis, an endemic disease of tropical and sub-tropical regions of the world. A recombinant γ-CA (BpsγCA) identified in the genome of this bacterium was cloned and purified. Its catalytic activity and anion inhibition profiles were investigated. The enzyme was an efficient catalyst for the CO2 hydration showing a kcat of 5.3×10(5)s(-1) and kcat/Km of 2.5×10(7)M(-1)×s(-1). The best BpsγCA inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed KI in the range of 49-83μM (these inhibitors showed millimolar inhibition constant against hCA II), followed by diethyldithiocarbamate, selenate, tellurate, perrhenate, selenocyanate, trithiocarbonate, tetraborato, pyrophosphate, stannate, carbonate, bicarbonate, azide, cyanide, thiocyanate and cyanate with KIs in the range of 0...
November 14, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27914364/structure-based-exploration-and-exploitation-of-the-s4-subsite-of-norovirus-3cl-protease-in-the-design-of-potent-and-permeable-inhibitors
#18
Anushka C Galasiti Kankanamalage, Yunjeong Kim, Athri D Rathnayake, Vishnu C Damalanka, Pathum M Weerawarna, Sean T Doyle, Amer F Alsoudi, D M Padmasankha Dissanayake, Gerald H Lushington, Nurjahan Mehzabeen, Kevin P Battaile, Scott Lovell, Kyeong-Ok Chang, William C Groutas
Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents...
November 14, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914362/an-overview-of-the-binding-models-of-fgfr-tyrosine-kinases-in-complex-with-small-molecule-inhibitors
#19
REVIEW
Weiyan Cheng, Mixiang Wang, Xin Tian, Xiaojian Zhang
The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors...
November 25, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914062/computational-design-of-ligand-binding-proteins
#20
Christine E Tinberg, Sagar D Khare
The ability to design novel small-molecule binding sites in proteins is a stringent test of our understanding of the principles of molecular recognition, and would have many practical applications, in synthetic biology and medicine. Here, we describe a computational method in the context of the macromolecular modeling suite Rosetta to designing proteins with sites featuring predetermined interactions to ligands of choice. The required inputs for the method are a model of the small molecule and the desired interactions (e...
2017: Methods in Molecular Biology
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