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https://www.readbyqxmd.com/read/29166086/focused-conformational-sampling-in-proteins
#1
Marco Bacci, Cassiano Langini, Jiří Vymětal, Amedeo Caflisch, Andreas Vitalis
A detailed understanding of the conformational dynamics of biological molecules is difficult to obtain by experimental techniques due to resolution limitations in both time and space. Computer simulations avoid these in theory but are often too short to sample rare events reliably. Here we show that the progress index-guided sampling (PIGS) protocol can be used to enhance the sampling of rare events in selected parts of biomolecules without perturbing the remainder of the system. The method is very easy to use as it only requires as essential input a set of several features representing the parts of interest sufficiently...
November 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#2
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rouge, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29165067/optimized-virtual-screening-workflow-towards-target-based-polynomial-scoring-functions-for-hiv-1-protease
#3
Val Oliveira Pintro, Walter F Azevedo
BACKGROUND: One key step in the development of inhibitors for an enzyme is the application of computational methodologies to predict protein-ligand interactions. The abundance of structural and ligand-binding information for HIV-1 protease opens up the possibility to apply computational methods to develop scoring functions targeted to this enzyme. OBJECTIVE: Our goal here is to develop an integrated molecular docking approach to investigate protein-ligand interactions with focus on the HIV-1 protease...
November 20, 2017: Combinatorial Chemistry & High Throughput Screening
https://www.readbyqxmd.com/read/29164104/targeting-dengue-virus-ns-3-helicase-by-ligand-based-pharmacophore-modeling-and-structure-based-virtual-screening
#4
Sobia A Halim, Shanza Khan, Ajmal Khan, Abdul Wadood, Fazal Mabood, Javid Hussain, Ahmed Al-Harrasi
Dengue fever is an emerging public health concern, with several million viral infections occur annually, for which no effective therapy currently exist. Non-structural protein 3 (NS-3) Helicase encoded by the dengue virus (DENV) is considered as a potential drug target to design new and effective drugs against dengue. Helicase is involved in unwinding of dengue RNA. This study was conducted to design new NS-3 Helicase inhibitor by in silico ligand- and structure based approaches. Initially ligand-based pharmacophore model was generated that was used to screen a set of 1201474 compounds collected from ZINC Database...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29161777/structure-based-design-and-evaluation-of-synthetic-porphyrin-derivatives-as-g-quadruplex-stabilizing-anticancer-agents
#5
R N Bhadane, D B Meshram, R M Gilhotra
G-quadruplex structures formed in telomeres and proto-oncogene represent a potentially useful target for anticancer drugs. Stabilization of this arrangement may inhibit the further action of different enzymes involved in cancer cell immortalization. In present work structure based drug design and synthesis was carried out on series of meso-substituted porphyrin analogues. The interaction of porphyrin derivatives with G-quadruplex DNA has been explored by virtual screening procedure. Some of the potential binding agents were then synthesized and evaluated in-vitro by MTT and PCR stop assay...
November 2017: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/29161155/the-use-of-virtual-communities-of-practice-to-improve-interprofessional-collaboration-and-education-findings-from-an-integrated-review
#6
Clodagh McLoughlin, Kunal D Patel, Tom O'Callaghan, Scott Reeves
The recent growth in online technology has led to a rapid increase in the sharing of health related information globally. Health and social care professionals are now using a wide range of virtual communities of practice (VCoPs) for learning, support, continuing professional education, knowledge management and information sharing. In this article, we report the findings from a review of the literature that explored the use of VCoPs by health and social care professionals to determine their potential for interprofessional education and collaboration...
November 21, 2017: Journal of Interprofessional Care
https://www.readbyqxmd.com/read/29159991/journey-to-the-centre-of-the-cell-virtual-reality-immersion-into-scientific-data
#7
REVIEW
Angus P R Johnston, James Rae, Nicholas Ariotti, Benjamin Bailey, Andrew Lija, Robyn Webb, Charles Ferguson, Sheryl Maher, Thomas P Davis, Richard I Webb, John McGhee, Robert G Parton
Visualization of scientific data is crucial not only for scientific discovery but also to communicate science and medicine to both experts and a general audience. Until recently, we have been limited to visualizing the three-dimensional (3D) world of biology in 2 dimensions. Renderings of 3D cells are still traditionally displayed using two-dimensional (2D) media, such as on a computer screen or paper. However, the advent of consumer grade virtual reality (VR) headsets such as Oculus Rift and HTC Vive means it is now possible to visualize and interact with scientific data in a 3D virtual world...
November 21, 2017: Traffic
https://www.readbyqxmd.com/read/29159859/identifiability-in-n-mixture-models-a-large-scale-screening-test-with-bird-data
#8
Marc Kéry
Binomial N-mixture models have proven very useful in ecology, conservation and monitoring: they allow estimation and modeling of abundance separately from detection probability using simple counts. Recently, doubts about parameter identifiability have been voiced. I conducted a large-scale screening test with 137 bird data sets from 2,037 sites. I found virtually no identifiability problems for Poisson and zero-inflated Poisson (ZIP) binomial N-mixture models, but negative-binomial (NB) models had problems in 25% of all data sets...
November 21, 2017: Ecology
https://www.readbyqxmd.com/read/29159521/discovery-of-small-molecules-binding-to-the-normal-conformation-of-prion-by-combining-virtual-screening-and-multiple-biological-activity-evaluation-methods
#9
Lanlan Li, Wei Wei, Wen-Juan Jia, Yongchang Zhu, Yan Zhang, Jiang-Huai Chen, Jiaqi Tian, Huanxiang Liu, Yong-Xing He, Xiaojun Yao
Conformational conversion of the normal cellular prion protein, PrP(C), into the misfolded isoform, PrP(Sc), is considered to be a central event in the development of fatal neurodegenerative diseases. Stabilization of prion protein at the normal cellular form (PrP(C)) with small molecules is a rational and efficient strategy for treatment of prion related diseases. However, few compounds have been identified as potent prion inhibitors by binding to the normal conformation of prion. In this work, to rational screening of inhibitors capable of stabilizing cellular form of prion protein, multiple approaches combining docking-based virtual screening, steady-state fluorescence quenching, surface plasmon resonance and thioflavin T fluorescence assay were used to discover new compounds interrupting PrP(C) to PrP(Sc) conversion...
November 20, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29157600/receptor-structure-based-discovery-of-non-metabolite-agonists-for-the-succinate-receptor-gpr91
#10
Mette Trauelsen, Elisabeth Rexen Ulven, Siv A Hjorth, Matjaz Brvar, Claudia Monaco, Thomas M Frimurer, Thue W Schwartz
OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools. METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed...
December 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29156382/discovery-of-selective-dengue-virus-inhibitors-using-combination-of-molecular-fingerprint-based-virtual-screening-protocols-structure-based-pharmacophore-model-development-molecular-dynamics-simulations-and-in-vitro-studies
#11
Shaher Bano Mirza, Regina Ching Hua Lee, Justin Jang Hann Chu, Ramin Ekhteiari Salmas, Thomas Mavromoustakos, Serdar Durdagi
Dengue virus is a major issue of tropical and sub-tropical regions. The proliferation of virus results in immense number of deaths each year because of unavailability of on-shelf drugs. This issue necessitates the design of novel anti-Dengue drugs. The protease enzyme pathway is the critical target for drug design due to its significance in the replication, survival and other cellular activities of Dengue virus. Keeping in mind the worsening situation regarding Dengue virus, approximately eighteen million drug-like compounds from the ZINC small molecule database have been screened against Nonstructural Protein 3 (NS3) previously by our group...
October 24, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29156380/structure-based-design-of-herg-neutral-antihypertensive-oxazalone-and-imidazolone-derivatives
#12
Busecan Aksoydan, Isik Kantarcioglu, Ismail Erol, Ramin Ekhteiari Salmas, Serdar Durdagi
Angiotensin II receptor type 1 (AT1) antagonists are the most recent drug class against hypertension. Recently first crystal structure of AT1 receptor is deposited to the protein data bank (PDB ID: 4YAY). In this work, several molecular screening methods such as molecular docking and de novo design studies were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor...
October 18, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29154212/consensus-scoring-model-for-the-molecular-docking-study-of-mtor-kinase-inhibitor
#13
Dong-Dong Li, Xiang-Feng Meng, Qiang Wang, Pan Yu, Lin-Guo Zhao, Zheng-Ping Zhang, Zhen-Zhong Wang, Wei Xiao
The discovery of mammalian target of rapamycin (mTOR) kinase inhibitors has always been a research hotspot of antitumor drugs. Consensus scoring used in the docking study of mTOR kinase inhibitors usually improves hit rate of virtual screening. Herein, we attempt to build a series of consensus scoring models based on a set of the common scoring functions. In this paper, twenty-five kinds of mTOR inhibitors (16 clinical candidate compounds and 9 promising preclinical compounds) are carefully collected, and selected for the molecular docking study used by the Glide docking programs within the standard precise (SP) mode...
November 6, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29153890/molecular-dynamics-assisted-pharmacophore-modeling-of-caspase-3-isatin-sulfonamide-complex-recognizing-essential-intermolecular-contacts-and-features-of-sulfonamide-inhibitor-class-for-caspase-3-binding
#14
Sivakumar Prasanth Kumar, Chirag N Patel, Prakash C Jha, Himanshu A Pandya
The identification of isatin sulfonamide as a potent small molecule inhibitor of caspase-3 had fuelled the synthesis and characterization of the numerous sulfonamide class of inhibitors to optimize for potency. Recent works that relied on the ligand-based approaches have successfully shown the regions of optimizations for sulfonamide scaffold. We present here molecular dynamics-based pharmacophore modeling of caspase-3-isatin sulfonamide crystal structure, to elucidate the essential non-covalent contacts and its associated pharmacophore features necessary to ensure caspase-3 optimal binding...
August 9, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29150011/optimization-of-crispr-cas9-genome-editing-for-loss-of-function-in-the-early-chick-embryo
#15
Shashank Gandhi, Michael L Piacentino, Felipe M Vieceli, Marianne E Bronner
The advent of CRISPR/Cas9 has made genome editing possible in virtually any organism, including those not previously amenable to genetic manipulations. Here, we present an optimization of CRISPR/Cas9 for application to early avian embryos with improved efficiency via a three-fold strategy. First, we employed Cas9 protein flanked with two nuclear localization signal sequences for improved nuclear localization. Second, we used a modified guide RNA (gRNA) scaffold that obviates premature termination of transcription and unstable Cas9-gRNA interactions...
December 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/29147910/therapeutic-activities-of-dj-1-and-its-binding-compounds-against-neurodegenerative-diseases
#16
Masatoshi Inden, Daijiro Yanagisawa, Masanori Hijioka, Hiroyoshi Ariga, Yoshihisa Kitamura
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Loss-of-function mutations in the gene encoding PARK7/DJ-1 were identified in familial PD. Wild-type DJ-1 acts as an oxidative stress sensor in neural cells. Previously, we identified binding compounds of DJ-1, including UCP0045037/compound A, UCP0054278/compound B, and compound-23 (comp-23), by in silico virtual screening. These compounds prevented oxidative stress-induced dopaminergic neuronal death and restored locomotion defects in animal models of PD...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29147652/identification-of-potent-chloride-intracellular-channel-protein-1-inhibitors-from-traditional-chinese-medicine-through-structure-based-virtual-screening-and-molecular-dynamics-analysis
#17
Wei Wang, Minghui Wan, Dongjiang Liao, Guilin Peng, Xin Xu, Weiqiang Yin, Guixin Guo, Funeng Jiang, Weide Zhong, Jianxing He
Chloride intracellular channel 1 (CLIC1) is involved in the development of most aggressive human tumors, including gastric, colon, lung, liver, and glioblastoma cancers. It has become an attractive new therapeutic target for several types of cancer. In this work, we aim to identify natural products as potent CLIC1 inhibitors from Traditional Chinese Medicine (TCM) database using structure-based virtual screening and molecular dynamics (MD) simulation. First, structure-based docking was employed to screen the refined TCM database and the top 500 TCM compounds were obtained and reranked by X-Score...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29144742/successful-identification-of-cardiac-troponin-calcium-sensitizers-using-a-combination-of-virtual-screening-and-roc-analysis-of-known-troponin-c-binders
#18
Melanie L Aprahamian, Svetlana B Tikunova, Morgan V Price, Andres F Cuesta, Jonathan P Davis, Steffen Lindert
Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin. Calcium binds to the N-terminal domain of troponin C (cNTnC) which initiates the process of contraction. Heart failure is a consequence of a disruption of this process. With the prevalence of this condition, a strong need exists to find novel compounds to increase the calcium sensitivity of cNTnC. Desirable are small chemical molecules that bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium sensitizing properties by possibly stabilizing cTnC in an open conformation...
November 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29144001/biological-evaluation-and-energetic-analyses-of-novel-gsk-3%C3%AE-inhibitors
#19
Denan Zhang, Lei Liu, Lin Pang, Qing Jin, Kehui Ke, Ming Hu, Jingbo Yang, Weifang Ma, Hongbo Xie, Xiujie Chen
Glycogen synthase kinase-3 beta (GSK-3β) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3β activity have been implicated in diabetes, heart disease, Parkinson disease and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3β were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29142426/in-silico-and-in-vitro-anticancer-activity-of-isolated-novel-marker-compound-from-chemically-modified-bioactive-fraction-from-curcuma-longa-nccl
#20
Arshi Naqvi, Richa Malasoni, Swati Gupta, Akansha Srivastava, Rishi R Pandey, Anil Kumar Dwivedi
Background: Turmeric (Curcuma longa) is reported to possess wide array of biological activities. Herbal Medicament (HM) is a standardized hexane-soluble fraction of C. longa and is well known for its neuroprotective effect. Objective: In this study, we attempted to synthesize a novel chemically modified bioactive fraction from HM (NCCL) along with isolation and characterization of a novel marker compound (I). Materials and Methods: NCCL was prepared from HM...
October 2017: Pharmacognosy Magazine
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