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https://www.readbyqxmd.com/read/28431339/novel-coumarin-and-quinolinone-based-polycycles-as-cell-division-cycle-25-a-and-c-phosphatases-inhibitors-induce-proliferation-arrest-and-apoptosis-in-cancer-cells
#1
Clemens Zwergel, Brigitte Czepukojc, Emilie Evain-Bana, Zhanjie Xu, Giulia Stazi, Mattia Mori, Alexandros Patsilinakos, Antonello Mai, Bruno Botta, Rino Ragno, Denise Bagrel, Gilbert Kirsch, Peter Meiser, Claus Jacob, Mathias Montenarh, Sergio Valente
Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397...
April 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28420580/comparative-pharmacodynamic-analysis-of-imidazoline-compounds-using-rat-model-of-ocular-mydriasis-with-a-test-of-quantitative-structure-activity-relationships
#2
Joanna Raczak-Gutknecht, Antoni Nasal, Teresa Frąckowiak, Anita Kornicka, Franciszek Sączewski, Renata Wawrzyniak, Łukasz Kubik, Roman Kaliszan
Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain...
April 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28420545/gqsar-modeling-and-combinatorial-library-generation-of-4-phenylquinazoline-2-carboxamide-derivatives-as-antiproliferative-agents-in-human-glioblastoma-tumors
#3
Debolina Goswami, Sukriti Goyal, Salma Jamal, Ritu Jain, Divya Wahi, Abhinav Grover
BACKGROUND: TSPO translocator protein, encoded in humans by the Tspo gene plays a crucial role in mitochondria mediated apoptosis and necrotic cell death through its association with Mitochondrial Permeability Transition pore (MPTP). It has been shown that this function can be exploited as a potential treatment for human Glioblastoma Multiforme. In this study, a novel robust fragment based QSAR model has been developed for a series of 4-phenylquinazoline-2-carboxamides experimentally known to be ligands for TSPO, thus triggering apoptotic mechanism cascade...
April 4, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28419798/pvloo-based-training-set-selection-improves-the-external-predictability-of-qsar-qspr-models
#4
Ying Dong, Bingren Xiang, Ding Du
In QSAR/QSPR modeling, the indispensable way to validate the predictability of a model is to perform its statistical external validation. It is common that division algorithm should be used to select training sets from chemical compound libraries or collections prior to external validations. In this study, division method based on the posterior variance of leave-one-out cross-validation (PVLOO) of Gaussian process (GP) has been developed with the goal of producing more predictive models. Four structurally diverse data sets of good quality are collected from the literature and then redeveloped and validated on the basis of training set selection methods, namely: four kinds of PVLOO based training set selection methods with three types of covariance functions (squared exponential, rational quadratic, and neural network covariance function), the Kennard-Stone algorithm and random division...
April 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28419717/ligand-recognition-properties-of-the-vasopressin-v2-receptor-studied-under-qsar-and-molecular-modeling-strategies
#5
Marlet Martínez-Archundia, Brenda Colín-Astudillo, L M Moreno-Vargas, G Ramírez-Galicia, R Garduño-Juárez, O Deeb, Martha C Contreras-Romo, A Quintanar-Stephano, Edgar Abarca-Rojano, José Correa-Basurto
The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease, etc. To get structural insights related to V2R-ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three-dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies...
April 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28418656/informing-the-selection-of-screening-hit-series-with-in-silico-absorption-distribution-metabolism-excretion-and-toxicity-profiles
#6
John M Sanders, Douglas C Beshore, J Chris Culberson, James I Fells, Jason E Imbriglio, Hakan Gunaydin, Andrew M Haidle, Marc Labroli, Brian E Mattioni, Nunzio Sciammetta, William D Shipe, Robert P Sheridan, Linda M Suen, Andreas Verras, Abbas M Walji, Elizabeth M Joshi, Tjerk Bueters
High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter...
April 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28418199/evaluation-of-biological-activity-and-computer-aided-design-of-new-soft-glucocorticoids
#7
Vladimir Dobričić, Vesna Jaćević, Jelica Vučićević, Katarina Nikolic, Sote Vladimirov, Olivera Čudina
Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone...
April 18, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28417668/exploring-molecular-structural-requirement-for-ache-inhibition-through-multi-chemometric-and-dynamics-simulation-analyses
#8
Tabassum Hossain, Achintya Saha, Arup Mukherjee
The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid β-peptide (Aβ) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-à-vis inhibiting enzyme activity...
April 18, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28412906/combined-approach-of-qsar-and-docking-studies-for-the-design-of-local-anaesthetic-agents
#9
S Zheng
BACKGROUND: Heterocyclic scaffold, benzotriazole and its derivatives are potential anaesthetic agents that are acting locally. OBJECTIVE: QSAR and docking analysis of previously synthesized benzotriazolyl derivatives were modelled for their local anaesthetic action using computer assisted multiple regression analysis. It provides the insight about the structural requirements for the local anaesthetic action. METHOD: A training set comprises of 16 molecules and test set of 8 molecules were selected for present investigation by using sphere exclusion method with dissimilarity value of +4...
April 13, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28412406/chemical-toxicity-prediction-for-major-classes-of-industrial-chemicals-is-it-possible-to-develop-universal-models-covering-cosmetics-drugs-and-pesticides
#10
Vinicius M Alves, Eugene N Muratov, Alexey Zakharov, Nail N Muratov, Carolina H Andrade, Alexander Tropsha
Computational models have earned broad acceptance for assessing chemical toxicity during early stages of drug discovery or environmental safety assessment. The majority of publicly available QSAR toxicity models have been developed for datasets including mostly drugs or drug-like compounds. We have evaluated and compared chemical spaces occupied by cosmetics, drugs, and pesticides, and explored whether current computational models of toxicity endpoints can be universally applied to all these chemicals. Our analysis of the chemical space overlap and applicability domain (AD) of models built previously for twenty different toxicity endpoints showed that most of these models afforded high coverage (>90%) for all three classes of compounds analyzed herein...
April 12, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28412404/development-of-human-biotransformation-qsars-and-application-for-pbt-assessment-refinement
#11
Ester Papa, Alessandro Sangion, Jon A Arnot, Paola Gramatica
Toxicokinetics heavily influence chemical toxicity as the result of Absorption, Distribution, Metabolism (Biotransformation) and Elimination (ADME) processes. Biotransformation (metabolism) reactions can lead to detoxification or, in some cases, bioactivation of parent compounds to more toxic chemicals. Moreover, biotransformation has been recognized as a key process determining chemical half-life in an organism and is thus a key determinant for bioaccumulation assessment for many chemicals. This study addresses the development of QSAR models for the prediction of in vivo whole body human biotransformation (metabolism) half-lives measured or empirically-derived for over 1000 chemicals, mainly represented by pharmaceuticals...
April 13, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28412023/precise-prediction-of-activators-for-the-human-constitutive-androstane-receptor-using-structure-based-three-dimensional-quantitative-structure-activity-relationship-methods
#12
Harutoshi Kato, Noriyuki Yamaotsu, Norihiko Iwazaki, Shigeaki Okamura, Toshiyuki Kume, Shuichi Hirono
The constitutive androstane receptor (CAR, NR1I3) regulates the expression of numerous drug-metabolizing enzymes and transporters. The upregulation of various enzymes, including CYP2B6, by CAR activators is a critical problem leading to clinically severe drug-drug interactions (DDIs). To date, however, few effective computational approaches for identifying CAR activators exist. In this study, we aimed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict the CAR activating potency of compounds emerging in the drug-discovery process...
February 9, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28411471/qsar-docking-studies-of-1-3-thiazinan-3-yl-isonicotinamide-derivatives-for-antitubercular-activity
#13
Trupti S Chitre, Kalyani D Asgaonkar, Shital M Patil, Shiva Kumar, Vijay M Khedkar, Dinesh R Garud
The enzyme - enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan-Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r(2)=0...
March 30, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28399673/pharmacophore-generation-atom-based-3d-qsar-and-molecular-dynamics-simulation-analyses-of-pyridine-3-carboxamide-6-yl-urea-analogues-as-potential-gyrase-b-inhibitors
#14
M A Azam, J Thathan
DNA gyrase subunit B (GyrB) is an attractive drug target for the development of antibacterial agents with therapeutic potential. In the present study, computational studies based on pharmacophore modelling, atom-based QSAR, molecular docking, free binding energy calculation and dynamics simulation were performed on a series of pyridine-3-carboxamide-6-yl-urea derivatives. A pharmacophore model using 49 molecules revealed structural and chemical features necessary for these molecules to inhibit GyrB. The best fitted model AADDR...
April 12, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28393626/in-silico-modelling-and-molecular-dynamics-simulation-studies-of-thiazolidine-based-ptp1b-inhibitors
#15
Manoj Kumar Mahapatra, Krishnendu Bera, Durg Vijay Singh, Rajnish Kumar, Manoj Kumar
Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signalling pathway, hence it can be considered as a new therapeutic target of intervention for the treatment of type2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e., diabestiy. In order to get more information on identification and optimisation of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold...
April 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28388567/synthesis-bioactivity-3d-qsar-studies-of-novel-dibenzofuran-derivatives-as-ptp-meg2-inhibitors
#16
Ying Ma, Hui-Yu Wei, Yu-Ze Zhang, Wen-Yan Jin, Hong-Lian Li, Hui-Zhou, Xian-Chao Cheng, Run-Ling Wang
PTP-MEG2 plays a critical role in the diverse cell signalling processes, so targeting PTP-MEG2 is a promising strategy for various human diseases treatments. In this study, a series of novel dibenzofuran derivatives was synthesized and assayed for their PTP-MEG2 inhibitory activities. 10a with highest inhibitory activity (320 nM) exhibited significant selectivity for PTP-MEG2 over its close homolog SHP2, CDC25 (IC50 > 50 μM). By means of the powerful ''HipHop'' technique, a 3D-QSAR study was carried out to explore structure activity relationship of these molecules...
March 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28385577/carbamates-and-ich-m7-classification-making-use-of-expert-knowledge
#17
Rachel Hemingway, Adrian Fowkes, Richard V Williams
Carbamates are widely used in the chemical industry so understanding their toxicity is important to safety assessment. Carbamates have been associated with certain toxicities resulting in publication of structural alerts, including alerts for mutagenicity. Structural alerts for bacterial mutagenicity can be used in combination with statistical systems to enable ICH M7 classification, which allows assessment of the genotoxic risk posed by pharmaceutical impurities. This study tested a hypothetical bacterial mutagenicity alert for carbamates and examined the impact it would have on ICH M7 classifications using QSAR predictions from the expert rule-based system Derek Nexus and the statistical-based system Sarah Nexus...
April 3, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28374255/qsar-modeling-and-chemical-space-analysis-of-antimalarial-compounds
#18
Pavel Sidorov, Birgit Viira, Elisabeth Davioud-Charvet, Uko Maran, Gilles Marcou, Dragos Horvath, Alexandre Varnek
Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models...
April 3, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28372912/novel-scaffold-evolution-through-combinatorial-3d-qsar-model-studies-of-two-types-of-jnk3-inhibitors
#19
Hoyong Jung, Waqar Aman, Jung-Mi Hah
JNK3 is an emerging target for neurodegenerative diseases including AD and PD, with histological selectivity. Specifically, in AD, JNK3 is the main protein kinase for APP phosphorylation, which is an important mechanism for Aβ processing, and a biomarker of Alzheimer's disease. Therefore, targeting JNK3 is a reasonable strategy for drug discovery in neurodegenerative diseases. In order to find a novel scaffold for JNK3 inhibitors, we performed 3D-QSAR modeling studies with two different JNK3 inhibitor series...
March 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28364658/novel-2-benzylthio-5-1-3-4-oxadiazol-2-yl-benzenesulfonamides-with-anticancer-activity-synthesis-qsar-study-and-metabolic-stability
#20
Jarosław Sławiński, Krzysztof Szafrański, Aneta Pogorzelska, Beata Żołnowska, Anna Kawiak, Katarzyna Macur, Mariusz Belka, Tomasz Bączek
A series of novel 2-benzylthio-4-chloro-5-(5-substituted 1,3,4-oxadiazol-2-yl)benzenesulfonamides (4-27) have been synthesized as potential anticancer agents. MTT assay was carried out to determine the cytotoxic activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa as well as to determine the influence on human keratinocyte cell line HaCaT. Relatively high (IC50: 7-17 μM) cytostatic activity and selectivity against HeLa cell line was found for compounds 6, 7, 9-11 and 16...
March 25, 2017: European Journal of Medicinal Chemistry
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