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Ligand Design

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https://www.readbyqxmd.com/read/30103000/from-stroke-to-neurodegenerative-diseases-the-multi-target-neuroprotective-effects-of-3-n-butylphthalide-and-its-derivatives
#1
REVIEW
Longjian Huang, Shan Wang, Fei Ma, Yong Zhang, Yuchen Peng, Changhong Xing, Yipu Feng, Xiaoliang Wang, Ying Peng
Discovering effective agents to slow or stop neurodegeneration is a challenging task. Over decades, only a few drugs were approved by Food and Drug Administration (FDA) and most ended in failure. The lessons learned have switched the strategy of drug discovery from designing highly selective ligands to a network pharmacology approach. This enables many natural products like butylphthalide (NBP) once again to be regarded as a valuable source of leads for drug discovery. In this review, we first start with the neuroprotective effects of NBPs on acute ischemic stroke, and later spread to their applications in major neurodegenerative diseases...
August 10, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/30102863/transport-mechanisms-of-butyrate-modified-nanoparticles-insight-into-easy-entry-hard-transcytosis-of-active-targeting-system-in-oral-administration
#2
Lei Wu, Yuli Bai, Min Liu, Lian Li, Wei Shan, Zhirong Zhang, Yuan Huang
The intestinal epithelium constitutes a major barrier for orally delivered nanoparticles (NPs). Although surface ligand modification can increase cellular uptake of NPs, the transepithelial transport of active targeting NPs is relatively limited. The phenomenon is described as "easy entry, hard transcytosis". Yet, underlying mechanisms and potential solutions of this phenomenon are unclear. Here, butyrate modified polyethylene glycol coated NPs (Bu-PEG NPs) were chosen as the model active targeting NPs...
August 13, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/30102391/insights-into-the-development-of-chemical-probes-for-rna
#3
Brittany S Morgan, Jordan E Forte, Amanda E Hargrove
Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND). In this survey, we examine the RNA targets, design and discovery strategies, and chemical probe characterization techniques of these ligands...
August 8, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/30101712/structure-based-drug-design-strategies-and-challenges
#4
Xing Wang, Ke Song, Li Li, Lijiang Chen
Over the past ten years, the number of three-dimensional protein structures identified by advanced science and technology increases, and the gene information becomes more available than ever before as well. The development of computing science becomes another driving force which makes it possible to use computational methods effectively in various phases of the drug design and research. Now Structure-based drug design (SBDD) tools are widely used to help researchers to predict the position of small molecules within a three-dimensional representation of the protein structure and estimate the affinity of ligands to target protein with considerable accuracy and efficiency...
August 13, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/30101151/a-library-based-screening-strategy-for-the-identification-of-darpins-as-ligands-for-receptor-targeted-aav-and-lentiviral-vectors
#5
Jessica Hartmann, Robert C Münch, Ruth-Therese Freiling, Irene C Schneider, Birgit Dreier, Washington Samukange, Joachim Koch, Markus A Seeger, Andreas Plückthun, Christian J Buchholz
Delivering genes selectively to the therapeutically relevant cell type is among the prime goals of vector development. Here, we present a high-throughput selection and screening process that identifies designed ankyrin repeat proteins (DARPins) optimally suited for receptor-targeted gene delivery using adeno-associated viral (AAV) and lentiviral (LV) vectors. In particular, the process includes expression, purification, and in situ biotinylation of the extracellular domains of target receptors as Fc fusion proteins in mammalian cells and the selection of high-affinity binders by ribosome display from DARPin libraries each covering more than 1012 variants...
September 21, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/30100693/synthesis-and-biological-investigations-of-3%C3%AE-aminotropane-arylamide-derivatives-with-atypical-antipsychotic-profile
#6
Jacek Stefanowicz, Tomasz Słowiński, Martyna Z Wróbel, Grzegorz Ślifirski, Maciej Dawidowski, Zdzisława Stefanowicz, Magdalena Jastrzębska-Więsek, Anna Partyka, Anna Wesołowska, Jadwiga Turło
This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β - aminotropane derivatives was evaluated for their affinity for 5-HT1A , 5-HT2A , and D2 receptors, which allowed for the identification of compounds 12e , 12i , and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies...
2018: Medicinal Chemistry Research
https://www.readbyqxmd.com/read/30100350/small-molecule-tlr8-antagonists-via-structure-based-rational-design
#7
Zhenyi Hu, Hiromi Tanji, Shuangshuang Jiang, Shuting Zhang, Kyoin Koo, Jean Chan, Kentaro Sakaniwa, Umeharu Ohto, Albert Candia, Toshiyuki Shimizu, Hang Yin
Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC50 values...
July 25, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/30099878/ph-regulated-optical-performances-in-organic-inorganic-hybrid-a-dual-mode-sensor-array-for-pattern-recognition-based-biosensing
#8
Qing Yan, Xu-Yin Ding, Zi-Han Chen, Shi-Fan Xue, Xin-Yue Han, Zi-Yang Lin, Miao Yang, Guoyue Shi, Min Zhang
Dual-mode optical assays are becoming more popular and attractive, since they would provide robust detailed information in biochemical analysis. We herein unveil a novel dual-mode optical (i.e. UV-vis absorption and fluorescence) method for multifunctional sensing of phosphate compounds (PCs) (e.g. nucleotides and pyrophosphate) based on pattern recognition, which innovatively employs only one kind of porphyrin/lanthanide-doped upconversion nanoparticles (Ln-UCNPs) hybrid integrated with a facile pH-regulated strategy as the sensor array...
August 13, 2018: Analytical Chemistry
https://www.readbyqxmd.com/read/30099251/thiabendazole-based-rh-iii-and-ir-iii-biscyclometallated-complexes-with-mitochondria-targeted-anticancer-activity-and-metal-sensitive-photodynamic-activity
#9
Cristina Pérez-Arnaiz, María Isabel Acuña, Natalia Busto, Igor Echevarría, Marta Martínez-Alonso, Gustavo Espino, Begoña García, Fernando Domínguez
Two pairs of Rh(III) and Ir(III) biscyclometallated complexes with thiabendazole (L1 ), named [Ir-a]Cl and [Rh-a]Cl, and N-benzyl-thiabendazole (L2 ), named [Ir-b]Cl and [Rh-b]Cl, have been designed and synthesized to explore the photophysical and biological effects that arise from changing both the metal center and the ancillary ligand. In the dark, the four metal complexes exhibit greater cytotoxicity than cisplatin against human colon (SW480) and human lung (A549) adenocarcinoma cell lines. Moreover, the pair of complexes bearing the ligand L2 is markedly more cytotoxic and present higher uptake values than complexes with L1 , thereby their biological properties were studied further to determine their mechanism of action...
August 2, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/30099123/selection-of-protein-conformations-for-structure-based-polypharmacology-studies
#10
REVIEW
Luca Pinzi, Fabiana Caporuscio, Giulio Rastelli
Several drugs exert their therapeutic effect through the modulation of multiple targets. Structure-based approaches hold great promise for identifying compounds with the desired polypharmacological profiles. These methods use knowledge of the protein binding sites to identify stereoelectronically complementary ligands. The selection of the most suitable protein conformations to be used in the design process is vital, especially for multitarget drug design in which the same ligand has to be accommodated in multiple binding pockets...
August 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/30098913/dual-targeting-for-brain-specific-liposomes-drug-delivery-system-synthesis-and-preliminary-evaluation
#11
Yao Peng, Yi Zhao, Yang Chen, Zhongzhen Yang, Li Zhang, Wenjiao Xiao, Jincheng Yang, Li Guo, Yong Wu
The treatment of glioma has become a great challenge because of the existence of brain barrier (BB). In order to develop an efficient brain targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs, a novel brain-targeted glucose-vitamin C (Glu-Vc) derivative was designed and synthesized as liposome ligand for preparing liposome to effectively deliver paclitaxel (PTX). The liposome was prepared and its particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis and cytotoxicity were also characterized...
August 4, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/30098884/spectroscopic-techniques-investigation-on-the-interaction-of-glucoamylase-with-1%C3%A2-deoxynojirimycin-mechanistic-and-conformational-study
#12
Hao Wu, Wei Zeng, Guiguang Chen, Ye Guo, Chengzhen Yao, Juan Li, Zhiqun Liang
1‑Deoxynojirimycin (DNJ), a representative polyhydroxylated alkaloids, is widely used in the field of antidiabetic, antitumor, and anti-HIV. The present study tried to clarify the interaction mechanism of DNJ with glucoamylase by multi-spectroscopic techniques, dynamic light scattering in combination with molecular modeling strategies from biophysics point of view. Fluorescence and UV-vis data indicated that fluorescence quenching mechanism of glucoamylase and DNJ was a dynamic manner. The association constant, binding site and thermodynamic parameters were also obtained from fluorescence spectrum at different temperatures...
August 7, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
https://www.readbyqxmd.com/read/30098463/aptasensor-designed-via-the-stochastic-tunneling-basin-hopping-method-for-biosensing-of-vascular-endothelial-growth-factor
#13
Hung-Wei Yang, Shin-Pon Ju, Che-Hao Cheng, Ying-Tzu Chen, Yu-Sheng Lin, See-Tong Pang
The Systematic Evolution Ligands by Exponential Enrichment (SELEX) is common used for selection of high affinity single-stranded DNA (ssDNA) aptamer with target protein. However, we do not know what the most stable configuration of the selected aptamer bound with target protein is. Therefore, a systematic search process using the stochastic tunneling-basin hopping (STUN-BH) method is proposed to find the most stable configuration of the ssDNA aptamer specific for vascular endothelial growth factor (VEGF) capture (AptVEGF ; 5'-TGTGGGGGTGGACGGGCCGGGTAGA-3')...
August 2, 2018: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/30098332/the-epidermal-growth-factor-receptor-structure-function-informing-the-design-of-anticancer-therapeutics
#14
REVIEW
Ruth A Mitchell, Rodney B Luwor, Antony W Burgess
Research on the epidermal growth factor (EGF) family and the family of receptors (EGFR) has progressed rapidly in recent times. New crystal structures of the ectodomains with different ligands, the activation of the kinase domain through oligomerisation and the use of fluorescence techniques have revealed profound conformational changes on ligand binding. The control of cell signaling from the EGFR-family is complex, with heterodimerisation, ligand affinity and signaling cross-talk influencing cellular outcomes...
August 8, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/30098158/on-stability-of-specific-adhesion-of-particles-to-membranes-in-simple-shear-flow
#15
Mohammad Hossein Moshaei, Mohammad Tehrani, Alireza Sarvestani
Adhesion of carrier particles to the luminal surface of endothelium under hemodynamic flow conditions is critical for successful vascular drug delivery. Endothelial cells line the inner surface of blood vessels. The effect of mechanical behavior of this compliant surface on the adhesion of blood-borne particles is unknown. In this contribution, we use a phase-plane method, first developed by Hammer and Lauffenburger [Biophysical Journal, 52, 475 (1987)], to analyze the stability of specific adhesion of a spherical particle to a compliant interface layer...
August 3, 2018: Journal of Biomechanical Engineering
https://www.readbyqxmd.com/read/30098083/tuning-gold-nanoparticles-with-chelating-ligands-for-highly-efficient-electrocatalytic-co2-reduction
#16
Zhi Cao, Samson B Zacate, Xiaodong Sun, Jinjia Liu, Elizabeth M Hale, William P Carson, Sam B Tyndall, Jun Xu, Xingwu Liu, Xingchen Liu, Chang Song, Jheng-Hua Luo, Mu-Jeng Cheng, Xiaodong Wen, Wei Liu
We report the capped chelating organic molecules as a design principle for tuning heterogeneous nanoparticles for electrochemical catalysis. Gold nanoparticles (AuNPs) functionalized with a chelating tetradentate porphyrin ligand show a 110-fold enhancement, compared to the oleylamine-coated AuNP, in current density for electrochemical reduction of CO2 to CO in water at an overpotential of 340 mV with Faradaic efficiencies (FEs) of 93%. These catalysts also show excellent stability without deactivation, <5% productivity loss, within 72 hours of electrolysis...
August 10, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/30097838/ligand-induced-symmetry-breaking-and-concomitant-blueshift-in-the-emission-wavelength-of-an-octahedral-chromium-complex
#17
Manoj Majumder, Satadal Paul, Anirban Misra
The resulting distortion of the octahedral symmetry of the complex [CrIII (NH3 )6 ]3+ upon replacing the axial ligands with halides (i.e., weaker ligands) affects the stability of the doublet state with respect to that of the quartet ground state. This substitution affects the doublet-to-quartet transition responsible for phosphorescence. The position of the halide with respect to ammonia in the spectrochemical series is a major influence on the emission wavelength of the complex. The close proximity of fluorine and ammonia in the spectrochemical series leads to a blueshift in the emission wavelength when fluoride ions are introduced into the complex, thus providing a rational approach to the design of blue-phosphorescent materials, which are desirable for OLEDs used in full-color displays...
August 11, 2018: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/30097591/computer-guided-surface-engineering-for-enzyme-improvement
#18
Matthew Wilding, Colin Scott, Andrew C Warden
Protein engineering strategies are often guided by our understanding of how the structure of a protein determines its function. However, our understanding is generally restricted to small regions of a protein, namely the active site and its immediate vicinity, while the remainder of the protein is something of an enigma. Studying highly homologous transaminases with strictly conserved active sites, but different substrate preferences and activities, we predict and experimentally validate that the surface of the protein far from the active site carries out a decisive role in substrate selectivity and catalytic efficiency...
August 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30097342/review-on-biomimetic-affinity-chromatography-with-short-peptide-ligands-and-its-application-to-protein-purification
#19
REVIEW
Yu-Ming Fang, Dong-Qiang Lin, Shan-Jing Yao
Biomimetic affinity chromatography with short peptide ligands, as a promising bioseparation technique, has great potential to protein separation and purification, which is based on highly specific biological interactions between specially-designed ligands and target proteins. Generally, short peptide ligands with the chain length ranging from two to nine amino acids could be divided into two types, linear peptide ligands and cyclic peptide ligands. To obtain the desired short peptide ligands, rational design strategies could be applied by knowing the 3-dimensional (3D) information of the receptors or just knowing the surface cavities and the active site of the receptors...
July 30, 2018: Journal of Chromatography. A
https://www.readbyqxmd.com/read/30096652/rapid-induction-of-apoptosis-in-tumor-cells-treated-with-a-new-platinum-ii-complex-based-on-amino-thiazolidinone
#20
Xue-Qing Song, Ya-Hong Liu, Jia Shao, Zhen-Lei Zhang, Cheng-Zhi Xie, Xin Qiao, Wei-Guo Bao, Jing-Yuan Xu
Thiazolidinone derivatives have been previously shown significant anti-cancer activities. Two amino-thiazolidinone complexes, [Pt(HTone)Cl] (1) and [Cu(HTone)Cl] (3) (HTone = (Z)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one) and one ethyl-modified [Pt(ETone)Cl2 ] (2) (ETone = (Z)-3-ethyl-2-((E)-(1-(pyridin-2-yl)ethylidene) hydrazono)thiazolidin-4-one)], were designed and synthesized in order to explore novel metal-based antitumor agents. MTT assay indicated that 1 and 3 were markedly cytotoxic to MCF-7, HepG-2 and NCI-H460 tumor cells, superior to both cisplatin and the HTone ligand...
August 1, 2018: European Journal of Medicinal Chemistry
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