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Ligand Design

Enamul Haque, Yusuke Yamauchi, Victor Malgras, Kakarla Raghava Reddy, Jin Woo Yi, Md Shahriar A Hossain, Jeonghun Kim
Graphene-organic frameworks (GOFs) is a new class of graphene-based materials in which structure and properties can be designed by controlling the length and concentration of organic ligands, comparable to their tunable metal-organic frameworks (MOFs) counterpart. The structural properties (e.g., surface area, pore volume) and physico-chemical properties (e.g., electronic, thermal, and mechanical) of GOFs can be tuned based on the synthetic conditions. Such GOFs are promising as the next generation of novel materials for a wide range of potential applications such as H2 storage, electronic devices, sensors, drug carriers, etc...
October 18, 2018: Chemistry, An Asian Journal
Kun Song, Jian Zhang
An orthosteric site is commonly viewed as the primary, functionally binding pocket on a receptor. Signal molecules, endogenous agonists, and substrates are recognized by and bind to the orthosteric site of a specific target, resulting in a biological effect. A malfunctioning active site on a crucial receptor has been confirmed as the culprit that causes many metabolic disturbances, neurologic disorders, and genetic diseases. A competitive inhibitor that has a stronger binding affinity can outcompete an orthosteric ligand...
2018: Methods in Molecular Biology
Saba Munawar, Monique J Windley, Edwin G Tse, Matthew H Todd, Adam P Hill, Jamie I Vandenberg, Ishrat Jabeen
The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+ ) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50 ) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50 ) prediction of identified hits...
2018: Frontiers in Pharmacology
Hamid Asiabi, Yadollah Yamini, Maryam Shamsayei, Esmaiel Saievar-Iranizad, Amir Bayat, Saeid Kamari Kaverlavani
Design and synthesis of effective electrocatalysts for oxygen reduction reaction in alkaline environments is critical to reduce energy losses in alkaline fuel cells. We have systematically evaluated new approaches for reducing the Pt content while retaining the activity of a Pt-based catalyst with hydrolytic phases containing hydroxide moieties in addition to metal ions and ligands. We report for the first time architectured organic-inorganic hybrid nanorod catalyst, which is fabricated by solvothermal reaction of K2 MCl4 (M = Pd, Pt) with picolinic acid (PA) (chelating agent) in the presence of FeCl2 ...
October 17, 2018: Scientific Reports
Yau Xin Yi, Anand Gaurav
INTRODUCTION: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identification of the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity. MATERIALS AND METHOD: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the target...
October 16, 2018: Current Drug Discovery Technologies
A K Halder
Multiple Quantitative Structure-Activity Relationship (QSAR) analysis is widely used in drug discovery for lead identification. Human Immunodeficiency Virus (HIV) protease is one of the key targets for the treatment of Acquired Immunodeficiency Syndrome (AIDS). One of the major challenges for the design of HIV-1 protease inhibitors (HIV PRIs) is to increase the inhibitory activities against the enzyme to a level where the problem associated to drug resistance may be considerably delayed. Herein, chemometric analyses were performed with 346 structurally diverse HIV PRIs with experimental bioactivities against a sub-type B mutant to develop highly predictable QSAR models and also to identify the effective structural determinants for higher affinity against HIV PR...
November 2018: SAR and QSAR in Environmental Research
Yueqi Wang, Abbas Khan, Aman Chandra Kaushik, Muhammad Junaid, Xuehong Zhang, Dong-Qing Wei
Phenazine compounds have good activity against Mycobacterium tuberculosis. Based on the reported activities that were obtained in Mycobacterium tuberculosis H37Rv, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was built to design novel compounds against MTB. A 5-fold cross-validation method and external validation were used to analyze the accuracy of forecasting. The model has a cross-validation coefficient q2 =0.7 and a non-cross-validation coefficient r2 =0.903, indicating that the model has good predictive possibility...
October 17, 2018: Journal of Biomolecular Structure & Dynamics
Eva Neuner, Marina Frener, Alexandra Lusser, Ronald Micura
For this study, we utilized class-I and class-II preQ1 -sensing riboswitches as model systems to decipher the structure-activity relationship of rationally designed ligand derivatives in vitro and in vivo. We found that synthetic preQ1 ligands with amino-modified side chains that protrude from the ligand-encapsulating binding pocket, and thereby potentially interact with the phosphate backbone in their protonated form, retain or even increase binding affinity for the riboswitches in vitro. They, however, led to significantly lower riboswitch activities in a reporter system in vivo in E...
October 18, 2018: RNA Biology
Dina Lakayan, Rob Haselberg, Rabah Gahoual, Govert W Somsen, Jeroen Kool
Monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) are highly potent biopharmaceuticals designed for targeted cancer therapies. mAbs and ADCs can undergo modifications during production and storage which may affect binding to target receptors, potentially altering drug efficacy. In this work, liquid chromatography was coupled online to surface plasmon resonance (LC-SPR) to allow label-free affinity evaluation of mAb and ADC sample constituents (size and charge variants), under near-native conditions...
October 17, 2018: Analytical and Bioanalytical Chemistry
Małgorzata Pierzchalska, Małgorzata Panek, Maja Grabacka
The method of organoid culture has become a tool widely used in gastrointestinal research, but so far, the migration of organoids derived from gut epithelium and formed in 3D Matrigel matrix has not been reported and studied. The intestinal epithelial tissue derived from 19-day-old chicken embryo was cultured in Matrigel and the dynamic properties of the forming organoids were analyzed by time-lapse image analysis. It was observed that about one in ten organoids actively moved through the matrix, at a speed of 10-20 μm/h...
October 16, 2018: Protoplasma
Mihil Patel, Virginia-Maria Vlahava, Simone K Forbes, Ceri A Fielding, Richard J Stanton, Eddie C Y Wang
Human cytomegalovirus (HCMV) is under constant selective pressure from the immune system in vivo . Study of HCMV genes that have been lost in the absence of, or genetically altered by, such selection can focus research toward findings of in vivo significance. We have been particularly interested in the most pronounced change in the highly passaged laboratory strains AD169 and Towne-the deletion of 13-15 kb of sequence (designated the UL /b' region) that encodes up to 22 canonical genes, UL133-UL150. At least 5 genes have been identified in UL /b' that inhibit NK cell function...
2018: Frontiers in Immunology
Alex Dickson
The interaction between a ligand and a protein involves a multitude of conformational states. To achieve a particular deeply bound pose, the ligand must search across a rough free-energy landscape with many metastable minima. Creating maps of the ligand binding landscape is a great challenge, as binding and release events typically occur on timescales that are beyond the reach of molecular simulation. The WExplore enhanced sampling method is well suited to build these maps because it is designed to broadly explore free-energy landscapes and is capable of simulating ligand release pathways that occur on timescales as long as minutes...
September 29, 2018: Biophysical Journal
Robin Bofinger, May Zaw-Thin, Nicholas J Mitchell, P Stephen Patrick, Cassandra Stowe, Ana Gomez-Ramirez, Helen C Hailes, Tammy L Kalber, Alethea B Tabor
The design, synthesis and formulation of non-viral gene delivery vectors is an area of renewed research interest. Amongst the most efficient non-viral gene delivery systems are lipopolyplexes, in which cationic peptides are co-formulated with plasmid DNA and lipids. One advantage of lipopolyplex vectors is that they have the potential to be targeted to specific cell types by attaching peptide targeting ligands on the surface, thus increasing both the transfection efficiency and selectivity for disease targets such as cancer cells...
October 16, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Pingyu Zhang, Huaiyi Huang
Recent work has shown that the chemical reactivity of osmium complexes can be finely tuned by the choice of osmium oxidation state, the ligands (including C- and N-bound), and the coordination geometry and stereochemistry, so opening up a wide range of new potential biological and medical applications. Osmium cancer therapeutics can have diverse modes of action and targets, including DNA interactions, redox modulation and protein inhibition. Polypyridyl Os(ii) compounds have potential advantages for luminescent cell imaging and photodynamic therapy due to their favourable photophysical and photochemical properties, such as long-wavelength metal-ligand charge transfer (MLCT) absorptions, high photostability and useful near-infrared (NIR) emission...
October 16, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Massimo Cametti, Arianna Rossetti, Martina Lippi, Javier Martí-Rujas, Alessandro Sacchetti
Ligands L1 and L2 have been designed, synthesized and used to build for the first time bispidine-based coordination polymers (CPs) in combination with Mn(II). The novel CPs have been structurally characterized by SC- and P-XRD techniques, showing that they are composed of 1D ribbon like chains which adopt various arrangements depending on the trapped solvent species. These materials show highly dynamic behavior as they undergo heterogeneous solid/liquid and solid/vapor multiple solvent exchange processes, comprising crystalline-amorphous-crystalline, selective adsorption and SC-to-SC transformations, where major structural reorganization of the 1D ribbons are observed...
October 16, 2018: Chemistry: a European Journal
Hemchandra Keshav Chaudhari, Akshta R Pahelkar
PA-824 analogues have been proposed on a promising approach for treating MDR/XDR tuberculosis. In order to understand the structural requirement of reported extended side chain analogues were studied to get insight into their structural requirements responsible for high affinity as a ligand-based pharmacophore, 3D-QSAR model have been developed. A structurally diverse set of 84 molecules was divided into 17 molecules of test set and rest of the 67 molecules of training set. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R2 = 0...
October 15, 2018: Infectious Disorders Drug Targets
Shengtao Lu, Wuguo Bi, Quanchao Du, Sheetal Sinha, Xiangyang Wu, Arnold Subrata, Surajit Bhattacharjya, Bengang Xing, Edwin K L Yeow
An intelligent drug release system that is triggered into action upon sensing the motion of swarmer P. mirabilis is introduced. The rational design of the drug release system focuses on a pNIPAAm-co-pAEMA copolymer that prevents drug leakage in a tobramycin-loaded mesoporous silica particle by covering its surface via electrostatic attraction. The copolymer chains are also conjugated to peptide ligands YVLWKRKRKFCFI-NH2 that display affinity to Gram-negative bacteria. When swarmer P. mirabilis cells approach and come in contact with the particle, the copolymer-YVLWKRKRKFCFI-NH2 binds to the lipopolysaccharides on the outer membrane of motile P...
October 15, 2018: Nature Communications
Robert J Morrison, Nicolas-George Katsantonis, Kevin M Motz, Alexander T Hillel, C Gaelyn Garrett, James L Netterville, Christopher T Wootten, Susan M Majka, Timothy S Blackwell, Wonder P Drake, Alexander Gelbard
Objective To characterize the phenotype and function of fibroblasts derived from airway scar in idiopathic subglottic stenosis (iSGS) and to explore scar fibroblast response to interleukin 17A (IL-17A). Study Design Basic science. Setting Laboratory. Subjects and Methods Primary fibroblast cell lines from iSGS subjects, idiopathic pulmonary fibrosis subjects, and normal control airways were utilized for analysis. Protein, molecular, and flow cytometric techniques were applied in vitro to assess the phenotype and functional response of disease fibroblasts to IL-17A...
October 16, 2018: Otolaryngology—Head and Neck Surgery
Ruyin Cao, Alejandro Giorgetti, Andreas Bauer, Bernd Neumaier, Giulia Rossetti, Paolo Carloni
Human G-protein coupled receptors (GPCRs) are important targets for pharmaceutical intervention against neurological diseases. Here, we use molecular simulation to investigate the key step in ligand recognition governed by the extracellular domains in the neuronal adenosine receptor type 2A (hA2A R), a target for neuroprotective compounds. The ligand is the high-affinity antagonist (4-(2-(7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)ethyl)phenol), embedded in a neuronal membrane mimic environment...
October 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Péter Ábrányi-Balogh, László Petri, Tímea Imre, Péter Szijj, Andrea Scarpino, Martina Hrast, Ana Mitrović, Urša Pečar Fonovič, Krisztina Németh, Hélène Barreteau, David I Roper, Kata Horváti, György G Ferenczy, Janko Kos, Janez Ilaš, Stanislav Gobec, György M Keserű
Targeted covalent inhibitors have become an integral part of a number of therapeutic protocols and are the subject of intense research. The mechanism of action of these compounds involves the formation of a covalent bond with protein nucleophiles, mostly cysteines. Given the abundance of cysteines in the proteome, the specificity of the covalent inhibitors is of utmost importance and requires careful optimization of the applied warheads. In most of the cysteine targeting covalent inhibitor programs the design strategy involves incorporating Michael acceptors into a ligand that is already known to bind non-covalently...
October 6, 2018: European Journal of Medicinal Chemistry
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