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Virtual screening

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https://www.readbyqxmd.com/read/28650658/a-potent-selective-and-cell-active-protein-arginine-methyltransferase-5-prmt5-inhibitor-developed-by-structure-based-virtual-screening-and-hit-optimization
#1
Ruifeng Mao, Jingwei Shao, Kongkai Zhu, Yuanyuan Zhang, Hong Ding, Chenhua Zhang, Zhe Shi, Hualiang Jiang, De-Qun Sun, Wenhu Duan, Cheng Luo
PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as anti-cancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0...
June 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28650638/identification-and-structure-activity-relationships-of-novel-compounds-that-potentiate-the-activities-of-antibiotics-in-escherichia-coli
#2
Keith M Haynes, Narges Abdali, Varsha Jhawar, Helen I Zgurskaya, Jerry M Parks, Adam T Green, Jerome Yves Baudry, Valentin V Rybenkov, Jeremy C Smith, John K Walker
In Gram-negative bacteria, efflux pumps are able to prevent effective cellular concentrations from being achieved for a number of antibiotics. Small molecule adjuvants that act as efflux pump inhibitors (EPIs) have the potential to reinvigorate existing antibiotics that are currently ineffective due to efflux mechanisms. Through a combination of rigorous experimental screening and in silico virtual screening we recently identified novel classes of EPIs that interact with the membrane fusion protein AcrA, a critical component of the AcrAB-TolC efflux pump in E...
June 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28645855/training-surgical-residents-with-a-haptic-robotic-central-venous-catheterization-simulator
#3
David F Pepley, Adam B Gordon, Mary A Yovanoff, Katelin A Mirkin, Scarlett R Miller, David C Han, Jason Z Moore
OJECTIVE: Ultrasound guided central venous catheterization (CVC) is a common surgical procedure with complication rates ranging from 5 to 21 percent. Training is typically performed using manikins that do not simulate anatomical variations such as obesity and abnormal vessel positioning. The goal of this study was to develop and validate the effectiveness of a new virtual reality and force haptic based simulation platform for CVC of the right internal jugular vein. DESIGN: A CVC simulation platform was developed using a haptic robotic arm, 3D position tracker, and computer visualization...
June 20, 2017: Journal of Surgical Education
https://www.readbyqxmd.com/read/28644986/designing-novel-inhibitors-against-histone-acetyltransferase-hat-%C3%A2-gcn5-of-plasmodium-falciparum
#4
Amarjeet Kumar, Krishanu Bhowmick, Kunwar Somesh Vikramdeo, Neelima Mondal, Naidu Subbarao, Suman Kumar Dhar
During active proliferation phase of intra-erythrocytic cycle, the genome of P. falciparum is regulated epigenetically and evolutionary conserved parasite-specific histone proteins are extensively acetylated. The reversible process of lysine acetylation, causing transcriptional activation and its deacetylation, causing transcriptional repression is regulated by balanced activities of HATs and HDACs. They are also known to regulate antigenic variations and gametocytic conversion in P. falciparum. These histone modifying enzymes have been identified as potential targets for development of anitmalarials in literature...
June 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28644406/an-updated-review-on-marine-anticancer-compounds-the-use-of-virtual-screening-for-the-discovery-of-small-molecule-cancer-drugs
#5
REVIEW
Verónica Ruiz-Torres, Jose Antonio Encinar, María Herranz-López, Almudena Pérez-Sánchez, Vicente Galiano, Enrique Barrajón-Catalán, Vicente Micol
Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action...
June 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28642635/virtual-screening-following-rational-drug-design-based-approach-for-introducing-new-anti-amyloid-beta-aggregation-agent
#6
Garshasb Rigi, Mohammad Vala Ashdar Nakhaei, Hoda Eidipour, Arshia Najimi, Fahimeh Tajik, Niloufar Taher, Kamran Yarahmadi
Amyloid β (Aβ) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Aβ molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Aβ molecules...
2017: Bioinformation
https://www.readbyqxmd.com/read/28641512/molecular-docking-and-molecular-dynamics-simulation-based-approach-to-explore-the-dual-inhibitor-against-hiv-1-reverse-transcriptase-and-integrase
#7
Subhash Chander, Rajan Kumar Pandey, Ashok Penta, Bhanwar Singh Choudhary, Manish Sharma, Ruchi Malik, Vijay Kumar Prajapati, Sankaranarayanan Murugesan
HIV integrase (IN) and reverse transcriptase (RT) are key enzymes for the replication of HIV-1. DNA polymerase and ribonuclease H (RNase H) are the two catalytic domains of HIV-1 RT which are validated as drug targets because of their essence for replication. IN and RNase H domain of RT share the striking structural similarity; it contains conserved DDE triad (two aspartates and one glutamate) and a pair of divalent Mg2+/Mn2+ ions at their catalytic core domain. Therefore, the search of compounds with dual inhibition of IN and RNase H can be the viable and more efficacious approach for the drug development against both wild and drug resistance strains of HIV...
June 15, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/28641235/computer-aided-training-sensorimotor-cortex-functions-in-humans-before-the-upper-limb-transplantation-using-virtual-reality-and-sensory-feedback
#8
Marek Kurzynski, Anna Jaskolska, Jaroslaw Marusiak, Andrzej Wolczowski, Przemyslaw Bierut, Lukasz Szumowski, Jerzy Witkowski, Katarzyna Kisiel-Sajewicz
One of the biggest problems of upper limb transplantation is lack of certainty as to whether a patient will be able to control voluntary movements of transplanted hands. Based on findings of the recent research on brain cortex plasticity, a premise can be drawn that mental training supported with visual and sensory feedback can cause structural and functional reorganization of the sensorimotor cortex, which leads to recovery of function associated with the control of movements performed by the upper limbs. In this study, authors - based on the above observations - propose the computer-aided training (CAT) system, which generating visual and sensory stimuli, should enhance the effectiveness of mental training applied to humans before upper limb transplantation...
June 15, 2017: Computers in Biology and Medicine
https://www.readbyqxmd.com/read/28636950/structural-evidence-of-quercetin-multi-target-bioactivity-a-reverse-virtual-screening-strategy
#9
Diego Carvalho, Margot Paulino, Fabio Polticelli, Florencia Arredondo, Robert J Williams, Juan A Abin-Carriquiry
The ubiquitous flavonoid quercetin is broadly recognized for showing diverse biological and health-promoting effects, such as anti-cancer, anti-inflammatory and cytoprotective activities. The therapeutic potential of quercetin and similar compounds for preventing such diverse oxidative stress-related pathologies has been generally attributed to their direct antioxidant properties. Nevertheless, accumulated evidence indicates that quercetin is also able to interact with multiple cellular targets influencing the activity of diverse signaling pathways...
June 19, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28636361/a-machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#10
Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential anti-resistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
June 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28635653/virtual-screening-against-phosphoglycerate-kinase-1-in-quest-of-novel-apoptosis-inhibitors
#11
Jie Xia, Bo Feng, Qianhang Shao, Yuhe Yuan, Xiang Simon Wang, Naihong Chen, Song Wu
Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28635345/avatar-assisted-therapy-a-proof-of-concept-pilot-study-of-a-novel-technology-based-intervention-to-treat-substance-use-disorders
#12
Michael S Gordon, Steven B Carswell, Mary Schadegg, Kayla Mangen, Kelly Merkel, Susan Tangires, Frank J Vocci
BACKGROUND: Avatar-assisted therapy (AAT) is a novel and emerging technology that uses the Internet to enable clinicians and clients in substance abuse treatment to participate in group counseling sessions from separate and remote locations in real time through the use of avatars and virtual environments. OBJECTIVES: The current study is a pilot proof-of-concept feasibility study involving individuals in outpatient substance abuse treatment. This report addresses two questions: (1) are individuals who present for substance abuse treatment interested in receiving AAT and (2) what factors are associated with better treatment success...
February 17, 2017: American Journal of Drug and Alcohol Abuse
https://www.readbyqxmd.com/read/28634927/nine-pairs-of-megastigmane-enantiomers-from-the-leaves-of-eucommia-ulmoides-oliver
#13
Jiankun Yan, Xuliu Shi, Paul Owusu Donkor, Huajie Zhu, Xiumei Gao, Liqin Ding, Feng Qiu
Nine pairs of megastigmane enantiomers (1a/1b-9a/9b), comprising two new compounds (6S,9R)-blumenol C (7b), (6S,9S)-blumenol C (8b), two pairs of enantiomers (+)-(6R)-eucomegastigmane A (1a), (-)-(6S)-eucomegastigmane A (1b), (+)-(3S,4S)-eucomegastigmane B (5a), (-)-(3R,4R)-eucomegastigmane B (5b) isolated by chiral resolution firstly, and twelve known compounds, were isolated from the leaves of Eucommia ulmoides Oliver. Their structures were elucidated based on extensive spectroscopic analysis. Absolute configurations of the megastigmane enantiomers were assigned by comparing experimental ECD and OR with calculated ECD and OR...
June 20, 2017: Journal of Natural Medicines
https://www.readbyqxmd.com/read/28634539/using-mhealth-technologies-to-improve-the-identification-of-behavioral-health-problems-in-urban-primary-care-settings
#14
Martha Staeheli, Robert H Aseltine, Elizabeth Schilling, Daren Anderson, Bruce Gould
INTRODUCTION: Behavioral health disorders remain under recognized and under diagnosed among urban primary care patients. Screening patients for such problems is widely recommended, yet is challenging to do in a brief primary care encounter, particularly for this socially and medically complex patient population. METHODS: In 2013, intervention patients at an urban Connecticut primary clinic were screened for post-traumatic stress disorder, depression, and risky drinking (n = 146) using an electronic tablet-based screening tool...
2017: SAGE Open Medicine
https://www.readbyqxmd.com/read/28632421/novel-urushiol-derivatives-as-hdac8-inhibitors-rational-design-virtual-screening-molecular-docking-and-molecular-dynamics-studies
#15
Hao Zhou, Chengzhang Wang, Tao Deng, Ran Tao, Wenjun Li
Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The compounds' binding affinity towards HDAC8 was screened by Glide docking. The highest-scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Ten compounds had Glide scores of -8...
June 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28632406/tailored-pharmacophore-model-to-enhance-virtual-screening-and-drug-discovery-a-case-study-on-the-identification-of-potential-inhibitors-against-drug-resistant-mycobacterium-tuberculosis-3r-hydroxyacyl-acp-dehydratases
#16
Kgothatso E Machaba, Ndumiso N Mhlongo, Yussif M Dokurugu, Mahmoud Es Soliman
AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28632393/the-antinociceptive-agent-sbfi-26-binds-to-anandamide-transporters-fabp5-and-fabp7-at-two-different-sites
#17
Hao-Chi Hsu, Simon Tong, Yuchen Zhou, Matthew W Elmes, Su Yan, Martin Kaczocha, Dale G Deutsch, Robert C Rizzo, Iwao Ojima, Huilin Li
Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an -truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at a resolution of 2.2 Å and 1.9 Å, respectively. We found that only (S)-SBFI-26 was present in the crystal structures...
June 20, 2017: Biochemistry
https://www.readbyqxmd.com/read/28630595/qsar-models-of-human-data-can-enrich-or-replace-llna-testing-for-human-skin-sensitization
#18
Vinicius M Alves, Stephen J Capuzzi, Eugene Muratov, Rodolpho C Braga, Thomas Thornton, Denis Fourches, Judy Strickland, Nicole Kleinstreuer, Carolina H Andrade, Alexander Tropsha
Skin sensitization is a major environmental and occupational health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. We have compiled, curated, analyzed, and compared the available human and LLNA data. Using these data, we have developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance...
December 21, 2016: Green Chemistry: An International Journal and Green Chemistry Resource: GC
https://www.readbyqxmd.com/read/28629986/identification-of-influenza-polymerase-inhibitors-targeting-polymerase-pb2-cap-binding-domain-through-virtual-screening
#19
Ming Liu, Chun-Yeung Lo, Guoxin Wang, Hak-Fun Chow, Jacky Chi-Ki Ngo, David Chi-Cheong Wan, Leo Lit-Man Poon, Pang-Chui Shaw
Influenza A virus is the major cause of epidemics and pandemics worldwide. In this study, virtual screening was used to identify compounds interacting with influenza A polymerase PB2 cap-binding domain (CBD). With a database of 21,351 small molecules, 28 candidate compounds were tested and one compound (225) was identified as hit compound. Compound 225 and three of its analogs (225D1, 426 and 426Br) were found to bind directly to PB2 CBD by surface plasmon resonance (SPR). The evaluation of compounds 426Br and 225 indicated that they could bind to PB2 CBD and inhibit influenza virus at low micromolar concentration...
June 16, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28629155/repositioning-fda-drugs-as-potential-cruzain-inhibitors-from-trypanosoma-cruzi-virtual-screening-in-vitro-and-in-vivo-studies
#20
Isidro Palos, Edgar E Lara-Ramirez, Julio Cesar Lopez-Cedillo, Carlos Garcia-Perez, Muhammad Kashif, Virgilio Bocanegra-Garcia, Benjamin Nogueda-Torres, Gildardo Rivera
Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies...
June 18, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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