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https://www.readbyqxmd.com/read/28432980/discovery-of-potential-inhibitor-against-human-acetylcholinesterase-a-molecular-docking-and-molecular-dynamics-investigation
#1
Surya Pratap Singh, Dwijendra Gupta
Alzheimer's disease (AD) is a progressive neurodegenerative disease of central nervous system among elderly people. Human acetylcholinesterase (hAChE), an important enzyme in neuronal signaling, is responsible for the degradation of acetylcholine which in turn prevents the post synaptic signal transmissions. hAChE has been an attractive target of drug discovery for the search of therapeutics against AD. In the recent past hAChE has become hot target for the investigation of new potential therapeutics. We performed virtual screening of entire database against hAChE...
April 12, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28432357/in-silico-drug-discovery-approach-targeting-receptor-tyrosine-kinase-like-orphan-receptor-1-for-cancer-treatment
#2
Onkar Nath, Archana Singh, Indrakant K Singh
Receptor tyrosine kinases (RTK) are important cell signaling molecules that influence many cellular processes. Receptor tyrosine kinase such as orphan receptor 1 (Ror1), a surface antigen, is a member of the RTK family of Ror, which plays a crucial role in cancers that have high-grade histology. As Ror1 has been implicated to be a potential target for cancer therapy, we selected this protein for further investigation. The secondary and tertiary structure of this protein was determined, which revealed that this protein contained three β-sheets, seven α-helices, and coils...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431169/spa-ln-a-scoring-function-of-ligand-nucleic-acid-interactions-via-optimizing-both-specificity-and-affinity
#3
Zhiqiang Yan, Jin Wang
Nucleic acids have been widely recognized as potential targets in drug discovery and aptamer selection. Quantifying the interactions between small molecules and nucleic acids is critical to discover lead compounds and design novel aptamers. Scoring function is normally employed to quantify the interactions in structure-based virtual screening. However, the predictive power of nucleic acid-ligand scoring functions is still a challenge compared to other types of biomolecular recognition. With the rapid growth of experimentally determined nucleic acid-ligand complex structures, in this work, we develop a knowledge-based scoring function of nucleic acid-ligand interactions, namely SPA-LN...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28429549/is-there-a-practical-role-for-a-virtual-bone-biopsy-using-high-resolution-imaging-of-bone-in-patients-with-chronic-kidney-disease
#4
Ashish K Sharma, Nigel D Toussaint
Renal osteodystrophy (ROD) refers to alterations in bone turnover, mineralisation, mass and microarchitecture in patients with chronic kidney disease (CKD) and represents the skeletal component of 'CKD-mineral and bone disorder'. Changes in bone structure lead to impaired bone quality, compromised bone strength and increased susceptibility to fractures with associated significant morbidity, mortality and financial cost. Diagnosis and management of ROD is hindered by the inadequacy of currently available diagnostic methods to interpret the complex pathophysiology...
March 2017: Nephrology
https://www.readbyqxmd.com/read/28427443/benserazide-a-dopadecarboxylase-inhibitor-suppresses-tumor-growth-by-targeting-hexokinase-2
#5
Wei Li, Mengzhu Zheng, Shuangping Wu, Suyu Gao, Mei Yang, Zhimei Li, Qiuxia Min, Weiguang Sun, Lixia Chen, Guangya Xiang, Hua Li
BACKGROUND: Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy. METHODS: Structure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity...
April 20, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28426940/prospective-assessment-of-virtual-screening-heuristics-derived-using-a-novel-fusion-score
#6
Dante A Pertusi, Gregory O'Donnell, Michelle F Homsher, Kelli Solly, Amita Patel, Shannon L Stahler, Daniel Riley, Michael F Finley, Eleftheria N Finger, Gregory C Adam, Juncai Meng, David J Bell, Paul D Zuck, Edward M Hudak, Michael J Weber, Jennifer E Nothstein, Louis Locco, Carissa Quinn, Adam Amoss, Brian Squadroni, Michelle Hartnett, Mee Ra Heo, Tara White, S Alex May, Evelyn Boots, Kenneth Roberts, Patrick Cocchiarella, Alex Wolicki, Anthony Kreamer, Peter S Kutchukian, Anne Mai Wassermann, Victor N Uebele, Meir Glick, Andrew Rusinko, J Christopher Culberson
High-throughput screening (HTS) is a widespread method in early drug discovery for identifying promising chemical matter that modulates a target or phenotype of interest. Because HTS campaigns involve screening millions of compounds, it is often desirable to initiate screening with a subset of the full collection. Subsequently, virtual screening methods prioritize likely active compounds in the remaining collection in an iterative process. With this approach, orthogonal virtual screening methods are often applied, necessitating the prioritization of hits from different approaches...
April 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28426652/cheminformatics-aided-discovery-of-small-molecule-protein-protein-interaction-ppi-dual-inhibitors-of-tumor-necrosis-factor-tnf-and-receptor-activator-of-nf-%C3%AE%C2%BAb-ligand-rankl
#7
Georgia Melagraki, Evangelos Ntougkos, Vagelis Rinotas, Christos Papaneophytou, Georgios Leonis, Thomas Mavromoustakos, George Kontopidis, Eleni Douni, Antreas Afantitis, George Kollias
We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure-based with ligand-based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos...
April 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28425495/the-biglen-gpr171-peptide-receptor-system-within-the-basolateral-amygdala-regulates-anxiety-like-behavior-and-contextual-fear-conditioning
#8
Erin N Bobeck, Ivone Gomes, Darlene Pena, Kirstie A Cummings, Roger L Clem, Mihaly Mezei, Lakshmi A Devi
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171, a recently deorphanized receptor for the abundant neuropeptide BigLEN, is expressed in the BLA, we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits, MS0021570_1, was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells, (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons, and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus...
April 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28425478/data-intensive-genome-level-analysis-for-identifying-novel-non-toxic-drug-targets-for-multi-drug-resistant-mycobacterium-tuberculosis
#9
Divneet Kaur, Rintu Kutum, Debasis Dash, Samir K Brahmachari
We report the construction of a novel Systems Biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in Mycobacterium tuberculosis (Mtb). This is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. In the 1623 sequenced Mtb strains, 890 metabolic genes identified through a systems approach in Mtb were evaluated for non-synonymous mutations. The 33 genes showed none or one variation in the entire 1623 strains, including 1084 Russian MDR strains...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28422491/discovery-of-novel-ligands-for-tnf-%C3%AE-and-tnf-receptor-1-through-structure-based-virtual-screening-and-biological-assay
#10
Si Chen, Zhiwei Feng, Yun Wang, Shifan Ma, Ziheng Hu, Peng Yang, Yifeng Chai, Xiang-Qun Sean Xie
Tumor Necrosis Factor alpha (TNF-α) is overexpressed in various diseases, and it has been a validated therapeutic target for autoimmune diseases. All therapeutics currently used targeting TNF-α are biomacromolecules, and limited numbers of TNF-α chemical inhibitors have been reported, which makes the identification of small molecule alternatives in urgent need. Recent studies mainly focused on identifying small molecules that directly bind to TNF-α or TNF receptor-1 (TNFR1), and/or inhibit the interaction between TNF-α and TNFR1, and/or regulate related signaling pathways...
April 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28422428/identification-of-novel-transthyretin-fibril-formation-inhibitors-using-structure-based-virtual-screening
#11
Gabriella Ortore, Adriano Martinelli
Transthyretin (TTR) is the primary carrier for thyroxine (T4) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study in the wild-type TTR crystal structures was planned; our aim was to design new ligands able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the specularity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure-based studies...
April 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28418199/evaluation-of-biological-activity-and-computer-aided-design-of-new-soft-glucocorticoids
#12
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/28416805/a-new-inhibitor-of-the-%C3%AE-arrestin-ap2-endocytic-complex-reveals-interplay-between-gpcr-internalization-and-signalling
#13
Alexandre Beautrait, Justine S Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M Heydenreich, Etienne Khoury, Martin Audet, Philippe P Roux, Dmitry B Veprintsev, Stéphane A Laporte, Michel Bouvier
In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes...
April 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28416275/cisplatin-analogs-confer-protection-against-cyanide-poisoning
#14
Anjali K Nath, Xu Shi, Devin L Harrison, Jordan E Morningstar, Sari Mahon, Adriano Chan, Patrick Sips, Jangwoen Lee, Calum A MacRae, Gerry R Boss, Matthew Brenner, Robert E Gerszten, Randall T Peterson
Cisplatin holds an illustrious position in the history of chemistry most notably for its role in the virtual cure of testicular cancer. Here we describe a role for this small molecule in cyanide detoxification in vivo. Cyanide kills organisms as diverse as insects, fish, and humans within seconds to hours. Current antidotes exhibit limited efficacy and are not amenable to mass distribution requiring the development of new classes of antidotes. The binding affinity of the cyanide anion for the positively charged metal platinum is known to create an extremely stable complex in vitro...
April 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28413953/calculating-water-thermodynamics-in-the-binding-site-of-proteins-applications-of-watermap-to-drug-discovery
#15
Daniel Cappel, Woody Sherman, Thijs Beuming
The ability to accurately characterize the solvation properties (water locations and thermodynamics) of biomolecules is of great importance to drug discovery. While crystallography, NMR, and other experimental techniques can assist in determining the structure of water networks in proteins and protein-ligand complexes, most water molecules are not fully resolved and accurately placed. Furthermore, understanding the energetic effects of solvation and desolvation on binding requires an analysis of the thermodynamic properties of solvent involved in the interaction between ligands and proteins...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28410781/virtual-screen-to-nmr-vs2nmr-discovery-of-fragment-hits-for-the-cbp-bromodomain
#16
Dimitrios Spiliotopoulos, Jian Zhu, Eike-Christian Wamhoff, Nicholas Deerain, Jean-Rémy Marchand, Jonas Aretz, Christoph Rademacher, Amedeo Caflisch
Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a correlation to aggressiveness. We have screened a library of nearly 1500 fragments by high-throughput docking into the CBP bromodomain followed by binding energy evaluation using a force field with electrostatic solvation. Twenty of the 39 fragments selected by virtual screening are positive in one or more ligand-observed nuclear magnetic resonance (NMR) experiments...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28409029/biophysical-approaches-facilitate-computational-drug-discovery-for-atp-binding-cassette-proteins
#17
REVIEW
Steven V Molinski, Zoltán Bozóky, Surtaj H Iram, Saumel Ahmadi
Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank...
2017: International Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28408230/discovery-of-lrrk2-inhibitors-by-using-an-ensemble-of-virtual-screening-methods
#18
Emanuela Gancia, Marcel De Groot, Brenda Burton, David E Clark
In this paper, we present the results of a ligand- and structure-based virtual screen targeting LRRK2, a kinase that has been implicated in Parkinson's disease. For the ligand-based virtual screen, the structures of 12 competitor compounds were used as queries for a variety of 2D and 3D searches. The structure-based virtual screen relied on homology models of LRRK2, as no X-ray structure is currently available in the public domain. From the virtual screening, 662 compounds were purchased, of which 35 showed IC50 values below 10μM in wild-type and/or mutant LRRK2 (a hit rate of 5...
April 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28407565/an-integrated-approach-towards-the-discovery-of-novel-non-nucleoside-leishmania-major-pteridine-reductase-1-inhibitors
#19
Franco Henrique Andrade Leite, Thamires Quadros Froes, Suellen Gonçalves da Silva, Evandro Italo Macêdo de Souza, Drielli Gomes Vital-Fujii, Gustavo Henrique Goulart Trossini, Samuel Silva da Rocha Pita, Marcelo Santos Castilho
Despite the fact that Leishmania ssp are pteridine auxotrophs, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major. On the other hand Pteridine Reductase 1 (PTR1) inhibitors proved to be lethal to the parasite. Aiming at identifying hits that lie outside the chemical space of known PTR1 inhibitors, pharmacophore models that differentiate true-binders from decoys and explain the structure-activity relationships of known inhibitors were employed to virtually screen the lead-like subset of ZINC database...
March 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28405240/targeting-the-ubiquitin-conjugating-enzyme-e2d4-for-cancer-drug-discovery-a-structure-based-approach
#20
Vishwanath Ramatenki, Ramakrishna Dumpati, Rajender Vadija, Santhiprada Vellanki, Sarita Rajender Potlapally, Rohini Rondla, Uma Vuruputuri
Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols...
April 2017: Journal of Chemical Biology
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