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Protein-protein docking

Hao Li, Fang Fang, Yunqi Liu, Liangmin Xue, Meng Wang, Ying Guo, Xiaowei Wang, Chao Tian, Junyi Liu, Zhili Zhang
Bridge homologation of the previously reported nonclassical two-carbon-bridged antifolate, 2,4-diamino-6-phenethylpyrido[3,2-d]pyrimidine (wm-5a), afforded the three-, four- and five-carbon-bridged antifolate analogues 3.1-3.5, 4.1-4.2 and 5.1-5.5. The target compounds, with substituents at various positions on the carbon bridges, were efficiently synthesized by aldol condensation or Wittig reaction and followed by reduction. Elongation of the two-carbon bridge to three-, four- or five-carbon bridges, and also saturation of the carbon bridges, provided compounds with good inhibitory activity against recombinant human DHFR (rhDHFR)...
April 19, 2018: Bioorganic & Medicinal Chemistry
Jin-Hua Guo, Ren-Wang Jiang, Jacob Lauwring Andersen, Mikael Esmann, Natalya U Fedosova
The information obtained from crystallized complexes of the Na+ ,K+ -ATPase with cardiotonic steroids (CTS) is not sufficient to explain differences in the inhibitory properties of CTS such as stereoselectivity of CTS-binding or effect of glycosylation on the preference to enzyme isoforms. The uncertainty is related to the spacial organization of the hydrophilic cavity at the entrance of the CTS-binding site. Therefore, there is a need to supplement the crystallographic description with data obtained in aqueous solution, where molecules have significant degree of flexibility...
April 24, 2018: FEBS Journal
Barbara Baro, Soraya Játiva, Inés Calabria, Judith Vinaixa, Joan-Josep Bech-Serra, Carolina de LaTorre, João Rodrigues, María Luisa Hernáez, Concha Gil, Silvia Barceló-Batllori, Martin R Larsen, Ethel Queralt
Background: Protein phosphatase 2A (PP2A) is a family of conserved serine/threonine phosphatases involved in several essential aspects of cell growth and proliferation. PP2ACdc55 phosphatase has been extensively related to cell cycle events in budding yeast, however few PP2ACdc55 substrates have been identified. Here, we performed a quantitative mass spectrometry approach to reveal new substrates of PP2ACdc55 phosphatase and new PP2A-related processes in mitotic arrested cells. Results: We identified 62 statistically significant PP2ACdc55 substrates involved mainly in actin-cytoskeleton organization...
April 24, 2018: GigaScience
K Kranthi Kumar, B Uma Devi, P Neeraja
In this study, cholesterol biotransformation gene-set of human steroidogenic acute regulatory protein-related lipid transfer (START) domains were evaluated from high-throughput gene screening approaches. It was shown that STARD1, STARD3 and STARD4 proteins are better effective transporters of cholesterol than STARD5 and STARD6 domains. Docking studies show a strong agreement with gene ontology enrichment data. According to both complementary strategies, it was found that only STARD1, STARD3 and STARD4 are potentially involved in cholesterol biotransformation in mitochondria through Ω1-loop of C-terminal α4-helical domain...
April 24, 2018: SAR and QSAR in Environmental Research
Michal Gwizdala, Joshua L Botha, Adjélé Wilson, Diana Kirilovsky, Rienk van Grondelle, Tjaart P J Krüger
Photosynthetic organisms have found various smart ways to cope with unexpected changes in light conditions. In many cyanobacteria, the lethal effects of a sudden increase in light intensity are mitigated mainly by the interaction between phycobilisomes (PBs) and the Orange Carotenoid Protein (OCP). The latter senses high light intensities by means of photoactivation and triggers thermal energy dissipation from the PBs. Due to the brightness of their emission, PBs can be characterized at the level of individual complexes...
April 24, 2018: Journal of Physical Chemistry Letters
Haresh Ajani, Josef Jansa, Cemal Köprülüoğlu, Pavel Hobza, Vladimír Kryštof, Antonín Lyčka, Martin Lepsik
We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities...
April 23, 2018: Journal of Molecular Recognition: JMR
Anita A Wasik, Sanna Lehtonen
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin resistance correlates with the development of albuminuria in non-diabetic and diabetic patients. There is also accumulating evidence that glomerular epithelial cells or podocytes are insulin sensitive and that insulin signaling in podocytes is essential for maintaining normal kidney function...
2018: Frontiers in Endocrinology
Xueliang Ge, Chandra Sekhar Mandava, Christoffer Lind, Johan Åqvist, Suparna Sanyal
The interaction between the ribosomal-stalk protein L7/12 (L12) and initiation factor 2 (IF2) is essential for rapid subunit association, but the underlying mechanism is unknown. Here, we have characterized the L12-IF2 interaction on Escherichia coli ribosomes using site-directed mutagenesis, fast kinetics, and molecular dynamics (MD) simulations. Fifteen individual point mutations were introduced into the C-terminal domain of L12 (L12-CTD) at helices 4 and 5, which constitute the common interaction site for translational GTPases...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Sören Swyter, Matthias Schiedel, Daria Monaldi, Sándor Szunyogh, Attila Lehotzky, Tobias Rumpf, Judit Ovádi, Wolfgang Sippl, Manfred Jung
Sirtuins are NAD+ -dependent protein deacylases capable of cleaving off acetyl as well as other acyl groups from the ɛ-amino group of lysines in histones and other substrate proteins. They have been reported as promising drug targets, and thus modulators of their activity are needed as molecular tools to uncover their biological function and as potential therapeutics. Here, we present new assay formats that complement existing assays for sirtuin biochemistry and cellular target engagement. Firstly, we report the development of a homogeneous fluorescence-based activity assay using unlabelled acylated peptides...
June 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Xiongxiong Liu, Ping Li, Ryoichi Hirayama, Yuzhen Niu, Xinguo Liu, Weiqiang Chen, Xiaodong Jin, Pengcheng Zhang, Fei Ye, Ting Zhao, Bingtao Liu, Qiang Li
BACKGROUND AND PURPOSE: Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions. MATERIALS AND METHODS: Human glioblastoma (GBM) cell lines with or without genistein pre-treatment were irradiated with high-LET carbon ions...
April 20, 2018: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Juan Wang, Jiacai Wu, Xumei Li, Haowei Liu, Jianli Qin, Zhun Bai, Bixia Chi, Chen Xu
Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells...
April 20, 2018: Journal of Proteomics
Claas Strecker, Bernd Meyer
Protein flexibility poses a major challenge to docking of potential ligands in that the binding site can adopt different shapes. Docking algorithms usually keep the protein rigid and only allow the ligand to be treated as flexible. However, a wrong assessment of the shape of the binding pocket can prevent a ligand from adapting a correct pose. Ensemble docking is a simple yet promising method to solve this problem: Ligands are docked into multiple structures and the results are subsequently merged. Selection of protein structures is a significant factor for this approach...
April 23, 2018: Journal of Chemical Information and Modeling
V Divya, V L Pushpa, S Sarithamol, K B Manoj
Cyclin Dependent Kinase 4 is a striking target for the proposal of anti-cancer drugs since its overexpression is associated with various types of cancers. In the present study, 2D and 3D atom based QSAR study were accomplished with 6 component PLS factor for 230 pyrido[2,3-d]pyramidine correspondents along with flexible ligand docking in the extra precision mode with the application of core constraints followed by the binding energy determinations. Kernel based partial least square analysis fitting with fingerprints initially created worthy models, among which the one with molprint2D fingerprints generated a noble model with a score value of 0...
April 14, 2018: Journal of Molecular Graphics & Modelling
Sabina Podlewska, Rafał Kafel, Enza Lacivita, Grzegorz Satała, Albert J Kooistra, Márton Vass, Chris de Graaf, Marcello Leopoldo, Andrzej J Bojarski, Stefan Mordalski
Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivity between selected serotonin receptor subtypes was carried out. Special attention was focused on 5-HT7 R and the cross-interactions between its ligands and the 5-HT1A R, 5-HT1B R, 5-HT2A R, 5-HT2B R, and 5-HT6 R subtypes...
April 6, 2018: European Journal of Medicinal Chemistry
Ting Yu, Pradeep Paudel, Su Hui Seong, Jeong Ah Kim, Hyun Ah Jung, Jae Sue Choi
The rhizome of Salvia miltiorrhiza has emerged as a rich source of natural therapeutic agents, and its several compounds are supposed to exhibit favorable effects on Alzheimer's disease (AD). The present work investigate the anti-AD potentials of 12 tanshinones, three salvianolic acids and three caffeic acid derivatives from S. miltiorrhiza via the inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Among the tested compounds, deoxyneocryptotanshinone (1), salvianolic acid A (13) and salvianolic acid C (15) displayed good inhibitory effect on BACE1 with IC50 values of 11...
April 13, 2018: Computational Biology and Chemistry
Margaret A Schwarz, Daniel D Lee, Seamus Bartlett
Higher eukaryotes have developed extensive compartmentalization of amino acid (aa) - tRNA coupling through the formation of a multi-synthetase complex (MSC) that is composed of eight aa-tRNA synthetases (ARS) and three scaffold proteins: aminoacyl tRNA synthetase complex interacting multifunctional proteins (AIMP1, 2 and 3). Lower eukaryotes have a much smaller complex while yeast MSC consists of only two ARS (MetRS and GluRS) and one ARS cofactor 1 protein, Arc1p (Simos et al., 1996), the homolog of the mammalian AIMP1...
April 18, 2018: International Journal of Biochemistry & Cell Biology
Parvin Taghipour, Mostafa Zakariazadeh, Maryam Sharifi, Jafar Ezzati Nazhad Dolatabadi, Abolfazl Barzegar
Bovine serum albumin (BSA) is the most abundant protein in the blood circulation and it is commonly used for drug delivery in blood. Therefore, we aim to study BSA interaction with erlotinib as an anticancer drug using surface plasmon resonance (SPR) and molecular modeling methods under physiological conditions (pH = 7.4). BSA immobilized on carboxymethyl dextran hydrogel Au chip (CMD) after activation with N-hydroxysuccinimide and N-ethyl-N-(3-diethylaminopropyl) carbodiimide and then the erlotinib binding to BSA at different concentrations was evaluated...
April 9, 2018: Journal of Photochemistry and Photobiology. B, Biology
Meng-Die Yang, Qiu-Xiang Xu, Lian-Bao Ye, Ming Li, Yu Feng, Wei-Qiang Chen
Based on the anticancer mechanism of biological alkylating agent, we designed and synthesized two alpha pinene derivatives:(1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl benzenesulfonate and (1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl 4-methylbenzenesulfonate, of which structures were confirmed by ¹H-NMR, HPLC and MS date. These two compounds showed a good inhibition of tumor cells' proliferation. Further, the computer siuulation of molecular docking and metabolic kinetics indicated that these two copounds may have stable molecular complexation with protein CDK2, which closely related to the cell cycle...
March 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Kang Dai, Xue-Jia Yi, Xian-Ju Huang, Azhar Muhammad, Mei Li, Jun Li, Guang-Zhong Yang, Yue Gao
Gentianaceae herb extracts have been widely used as food additives, teas or medicinal remedies for various diseases and disorders of the human body. Herein, the potential effects of iridoids, seco-iridoids and analog glycosides from gentian on acontine-induced hepatotoxicity were investigated in HepG2 cells to obtain metabolic data of drug-biotarget interactions. Molecular docking analysis was performed to assess the binding efficiencies of 53 iridoids, seco-iridoids and analog compounds obtained from 50 gentian species to the active sites of human CYP3A4 enzyme...
April 20, 2018: Food & Function
Matthias Richard, Ana Victoria Gutiérrez, Albertus J Viljoen, Eric Ghigo, Mickael Blaise, Laurent Kremer
Mycobacterium abscessus is an emerging human pathogen causing severe pulmonary infections and is refractory to standard antibiotherapy, yet few drug resistance mechanisms have been reported in this organism. Recently, mutations in MAB_4384 leading to up-regulation of the MmpS5/MmpL5 efflux pump were linked to increased resistance to thiacetazone derivatives. Herein, the DNA-binding activity of MAB_4384 was investigated by electrophoretic mobility shift assays using the palindromic sequence IRS5/L5 located upstream of mmpS5/mmpL5 ...
2018: Frontiers in Microbiology
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