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Small molecule structure

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https://www.readbyqxmd.com/read/28922400/protein-folding-misfolding-and-aggregation-the-importance-of-two-electron-stabilizing-interactions
#1
Andrzej Stanisław Cieplak
Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates' morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer's and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure...
2017: PloS One
https://www.readbyqxmd.com/read/28921842/anchorquery-rapid-online-virtual-screening-for-small-molecule-protein-protein-interaction-inhibitors
#2
David R Koes, Alexander Dömling, Carlos J Camacho
AnchorQuery ( http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue...
September 16, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28921650/antibody-drug-conjugates-as-cancer-therapeutics-past-present-and-future
#3
Heather E Vezina, Monette Cotreau, Tae H Han, Manish Gupta
Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28920983/unified-elucidation-of-the-entropy-driven-and-opposed-hydrophobic-effects
#4
Masahiro Kinoshita, Tomohiko Hayashi
The association of nonpolar solutes is generally believed to be entropy driven, which has been shown to be true for the contact of small molecules, ellipsoids, and plates. However, it has been reported with surprise that a model cavity-ligand binding is entropy opposed. How can these apparently conflicting behaviors be elucidated? Here, we calculate the potential of mean force between hard-sphere solutes with various diameters in water and its entropic and enthalpic components using a statistical-mechanical theory for molecular liquids...
September 18, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28920684/stilbene-boronic-acids-form-a-covalent-bond-with-human-transthyretin-and-inhibit-its-aggregation
#5
Thomas P Smith, Ian W Windsor, Katrina T Forest, Ronald T Raines
Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes...
September 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28919443/fv-clasp-an-artificially-designed-small-antibody-fragment-with-improved-production-compatibility-stability-and-crystallizability
#6
Takao Arimori, Yu Kitago, Masataka Umitsu, Yuki Fujii, Ryoko Asaki, Keiko Tamura-Kawakami, Junichi Takagi
Antibody fragments are frequently used as a "crystallization chaperone" to aid structural analysis of complex macromolecules that are otherwise crystallization resistant, but conventional fragment formats have not been designed for this particular application. By fusing an anti-parallel coiled-coil structure derived from the SARAH domain of human Mst1 kinase to the variable region of an antibody, we succeeded in creating a novel chimeric antibody fragment of ∼37 kDa, termed "Fv-clasp," which exhibits excellent crystallization compatibility while maintaining the binding ability of the original IgG molecule...
September 6, 2017: Structure
https://www.readbyqxmd.com/read/28918607/modeling-the-ph-and-temperature-dependence-of-aqueousphase-hydroxyl-radical-reaction-rate-constants-of-organic-micropollutants-using-qspr-approach
#7
Shikha Gupta, Nikita Basant
Designing of advanced oxidation process (AOP) requires knowledge of the aqueous phase hydroxyl radical ((●)OH) reactions rate constants (k OH), which are strictly dependent upon the pH and temperature of the medium. In this study, pH- and temperature-dependent quantitative structure-property relationship (QSPR) models based on the decision tree boost (DTB) approach were developed for the prediction of k OH of diverse organic contaminants following the OECD guidelines. Experimental datasets (n = 958) pertaining to the k OH values of aqueous phase reactions at different pH (n = 470; 1...
September 16, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28918311/structural-basis-for-the-potent-and-selective-binding-of-ldn-212854-to-the-bmp-receptor-kinase-alk2
#8
Eleanor Williams, Alex N Bullock
Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2...
September 12, 2017: Bone
https://www.readbyqxmd.com/read/28917147/combined-in-silico-approaches-for-the-identification-of-novel-inhibitors-of-human-islet-amyloid-polypeptide-hiapp-fibrillation
#9
Palak Patel, Krupali Parmar, Vivek K Vyas, Dhaval Patel, Mili Das
Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the β-cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated β-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of β-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question...
September 6, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28916338/structure-activity-relationship-study-of-small-molecule-inhibitors-of-the-deptor-mtor-interaction
#10
Jihye Lee, Yijiang Shi, Mario Vega, Yonghui Yang, Joseph Gera, Michael E Jung, Alan Lichtenstein
DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase within mTORC1 and mTORC2 complexes. Over-expression of DEPTOR specifically occurs in the multiple myeloma (MM) tumor model and DEPTOR knockdown is cytotoxic to MM cells, suggesting it is a potential therapeutic target. Since mTORC1 paralysis protects MM cells against DEPTOR knockdown, it indicates that the protein-protein interaction between DEPTOR and mTOR is key to MM viability vs death. In a previous study, we used a yeast two-hybrid screen of a small inhibitor library to identify a compound that inhibited DEPTOR/mTOR binding in yeast...
September 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28915755/defects-and-oxidation-of-group-iii-monochalcogenide-monolayers
#11
Yu Guo, Si Zhou, Yizhen Bai, Jijun Zhao
Among various two-dimensional (2D) materials, monolayer group-III monochalcogenides (GaS, GaSe, InS, and InSe) stand out owing to their potential applications in microelectronics and optoelectronics. Devices made of these novel 2D materials are sensitive to environmental gases, especially O2 molecules. To address this critical issue, here we systematically investigate the oxidization behaviors of perfect and defective group-III monochalcogenide monolayers by first-principles calculations. The perfect monolayers show superior oxidation resistance with large barriers of 3...
September 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28915734/ce-in-the-4-oxidation-state-anion-photoelectron-spectroscopy-and-photodissociation-of-small-cexoyhz-molecules
#12
Josey E Topolski, Jared O Kafader, Caroline Chick Jarrold
The anion photoelectron (PE) spectra of a range of small mono-cerium molecular species, along with the Ce2O4(-) and Ce3O6(-) stoichiometric clusters, are presented and analyzed with the support of density functional theory calculations. A common attribute of all of the neutral species is that the Ce centers in both the molecules and clusters are in the +4 oxidation state. In bulk ceria (CeO2), an unoccupied, narrow 4f band lies between the conventional valence (predominantly O 2p) and conduction (Ce 5d) bands...
September 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28915537/mta1-expression-in-human-cancers-clinical-and-pharmacological-significance
#13
REVIEW
Vijaya Lakshmi Malisetty, Vasudevarao Penugurti, Prashanth Panta, Suresh Kumar Chitta, Bramanandam Manavathi
Remarkably, majority of the cancer deaths are due to metastasis, not because of primary tumors. Metastasis is one of the important hallmarks of cancer. During metastasis invasion of primary tumor cells from the site of origin to a new organ occurs. Metastasis associated proteins (MTAs) are a small family of transcriptional coregulators that are closely associated with tumor metastasis. These proteins are integral components of nuclear remodeling and deacetylation complex (NuRD). By virtue of being integral components of NuRD, these proteins regulate the gene expression by altering the epigenetic changes such as acetylation and methylation on the target gene chromatin...
September 11, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28915331/dual-specificity-phosphatase-5-substrate-interaction-a-mechanistic-perspective
#14
Raman G Kutty, Marat R Talipov, Robert D Bongard, Rachel A Jones Lipinski, Noreena L Sweeney, Daniel S Sem, Rajendra Rathore, Ramani Ramchandran
The mammalian genome contains approximately 200 phosphatases that are responsible for catalytically removing phosphate groups from proteins. In this review, we discuss dual specificity phosphatase 5 (DUSP5). DUSP5 belongs to the dual specificity phosphatase (DUSP) family, so named after the family members' abilities to remove phosphate groups from serine/threonine and tyrosine residues. We provide a comparison of DUSP5's structure to other DUSPs and, using molecular modeling studies, provide an explanation for DUSP5's mechanistic interaction and specificity toward phospho-extracellular regulated kinase, its only known substrate...
September 12, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28913782/docking-of-small-molecules-to-farnesoid-x-receptors-using-autodock-vina-with-the-convex-pl-potential-lessons-learned-from-d3r-grand-challenge-2
#15
Maria Kadukova, Sergei Grudinin
The 2016 D3R Grand Challenge 2 provided an opportunity to test multiple protein-ligand docking protocols on a set of ligands bound to farnesoid X receptor that has many available experimental structures. We participated in the Stage 1 of the Challenge devoted to the docking pose predictions, with the mean RMSD value of our submission poses of 2.9 Å. Here we present a thorough analysis of our docking predictions made with AutoDock Vina and the Convex-PL rescoring potential by reproducing our submission protocol and running a series of additional molecular docking experiments...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28913661/discovery-of-non-peptidic-small-molecule-inhibitors-of-cyclophilin-d-as-neuroprotective-agents-in-a%C3%AE-induced-mitochondrial-dysfunction
#16
Insun Park, Ashwini M Londhe, Ji Woong Lim, Beoung-Geon Park, Seo Yun Jung, Jae Yeol Lee, Sang Min Lim, Kyoung Tai No, Jiyoun Lee, Ae Nim Pae
Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to β amyloid (Aβ) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD)...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28913175/regulation-of-endoplasmic-reticulum-mitochondria-ca-2-transfer-and-its-importance-for-anti-cancer-therapies
#17
REVIEW
Gaia Pedriali, Alessandro Rimessi, Luigi Sbano, Carlotta Giorgi, Mariusz R Wieckowski, Maurizio Previati, Paolo Pinton
Inter-organelle membrane contact sites are emerging as major sites for the regulation of intracellular Ca(2+) concentration and distribution. Here, extracellular stimuli operate on a wide array of channels, pumps, and ion exchangers to redistribute intracellular Ca(2+) among several compartments. The resulting highly defined spatial and temporal patterns of Ca(2+) movement can be used to elicit specific cellular responses, including cell proliferation, migration, or death. Plasma membrane (PM) also can directly contact mitochondria and endoplasmic reticulum (ER) through caveolae, small invaginations of the PM that ensure inter-organelle contacts, and can contribute to the regulation of numerous cellular functions through scaffolding proteins such as caveolins...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28912562/flexible-supercapacitor-electrodes-based-on-real-metal-like-cellulose-papers
#18
Yongmin Ko, Minseong Kwon, Wan Ki Bae, Byeongyong Lee, Seung Woo Lee, Jinhan Cho
The effective implantation of conductive and charge storage materials into flexible frames has been strongly demanded for the development of flexible supercapacitors. Here, we introduce metallic cellulose paper-based supercapacitor electrodes with excellent energy storage performance by minimizing the contact resistance between neighboring metal and/or metal oxide nanoparticles using an assembly approach, called ligand-mediated layer-by-layer assembly. This approach can convert the insulating paper to the highly porous metallic paper with large surface areas that can function as current collectors and nanoparticle reservoirs for supercapacitor electrodes...
September 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28912274/structure-mechanism-and-regulation-of-polycomb-repressive-complex-2
#19
Lindsay E Moritz, Raymond C Trievel
Polycomb Repressive Complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this review, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials...
September 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28911847/analysis-of-structural-features-contributing-to-weak-affinities-of-ubiquitin-protein-interactions
#20
REVIEW
Ariel Cohen, Eran Rosenthal, Julia M Shifman
Ubiquitin is a small protein that enables one of the most common post-translational modifications, where the whole ubiquitin molecule is attached to various target proteins, forming mono- or polyubiquitin conjugations. As a prototypical multispecific protein, ubiquitin interacts non-covalently with a variety of proteins in the cell, including ubiquitin modifying enzymes and ubiquitin receptors that recognize signals from ubiquitin-conjugated substrates. To enable recognition of multiple targets and to support fast dissociation from the ubiquitin modifying enzymes, ubiquitin/protein interactions are characterized with low affinities, frequently in the higher μM and lower mM range...
September 11, 2017: Journal of Molecular Biology
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