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Virtual screening

Y Liu, L Huang, H Ye, X Lv
Interferon regulatory factor-7 (IRF-7) is involved in pulmonary infection and pneumonia. Here, a synthetic strategy that combined quantitative structure-activity relationship (QSAR)-based virtual screening and in vitro binding assay was described to identify new and potent mediator ligands of IRF-7 from natural products. In the procedure, a QSAR scoring function was developed and validated using Gaussian process (GP) regression and a structure-based set of protein-ligand affinity data. By integrating hotspot pocket prediction, pharmacokinetics profile analysis and molecular docking calculations, the scoring function was successfully applied to virtual screening against a large library of structurally diverse, drug-like natural products...
October 20, 2016: SAR and QSAR in Environmental Research
Jonathan M Scott, Stephen E Robinson, Tom Holroyd, Richard Coppola, Susumu Sato, Sara K Inati
PURPOSE: To describe and optimize an automated beamforming technique followed by identification of locations with excess kurtosis (g2) for efficient detection and localization of interictal spikes in patients with medically refractory epilepsy. METHODS: Synthetic aperture magnetometry with g2 averaged over a sliding time window (SAMepi) was performed in seven patients with focal epilepsy and five healthy volunteers. The effect of varied window lengths on detection of spiking activity was evaluated...
October 2016: Journal of Clinical Neurophysiology: Official Publication of the American Electroencephalographic Society
Baki Vijaya Bhaskar, Tirumalasetty Muni Chandra Babu, Netala Vasudeva Reddy, Wudayagiri Rajendra
Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer...
2016: Drug Design, Development and Therapy
Mohammad A Ghattas, Noor Raslan, Asil Sadeq, Mohammad Al Sorkhy, Noor Atatreh
Protein tyrosine phosphatases (PTP) play important roles in the pathogenesis of many diseases. The fact that no PTP inhibitors have reached the market so far has raised many questions about their druggability. In this study, the active sites of 17 PTPs were characterized and assessed for its ability to bind drug-like molecules. Consequently, PTPs were classified according to their druggability scores into four main categories. Only four members showed intermediate to very druggable pocket; interestingly, the rest of them exhibited poor druggability...
2016: Drug Design, Development and Therapy
Dar-Chone Chow, Kacie Rice, Wanzhi Huang, Robert L Atmar, Timothy G Palzkill
The β-lactamase inhibitory protein (BLIP) binds and inhibits a wide range of class A β-lactamases including the TEM-1 β-lactamase (Ki= 0.5 nM), which is widely present in Gram-negative bacteria, and the KPC-2 β-lactamase (Ki= 1.2 nM), which hydrolyzes virtually all clinically useful β-lactam antibiotics. The extent to which the specificity of a protein that binds a broad range of targets can be modified to display narrow specificity was explored in this study by engineering BLIP to bind selectively to KPC-2 β-lactamase...
October 18, 2016: ACS Infectious Diseases
Sanjay Kumar Dey, Pankaj Prabhakar, Manisha Saini, Toyanji Joseph, B K Thelma, Subir K Maulik, Suman Kundu
OBJECTIVE: To identify novel inhibitors of dopamine beta hydroxylase (DBH) and evaluate their antihypertensive properties in L-NAME induced hypertensive rat model. DESIGN AND METHOD: An experimentally validated computational model for hDBH, built in our lab, was used for structure-based, rational drug-design. The three-dimensional model was used for virtual-screening against small molecule databases from NCI, USA and elsewhere. Identified top hits were then tested in vitro against DBH with known inhibitors nepicastat and disulfiram as controls...
September 2016: Journal of Hypertension
Kunal Zaveri, Kiranmayi Patnala
BACKGROUND: The prevalence of multi-drug resistance S. aureus is one most challenging task for treatment of nosocomial infections. Proteins and enzymes of peptidoglycan biosynthesis pathway are one among the well-studied targets, but many of the enzymes are unexplored as targets. MurE is one such enzyme featured to be a promising target. As MurE plays an important role in ligating the L-lys to stem peptide at third position that is crucial for peptidoglycan synthesis. OBJECTIVE: To screen the potential MurE inhibitor...
October 10, 2016: Current Computer-aided Drug Design
Sean Ekins, John Liebler, Bruno J Neves, Warren G Lewis, Megan Coffee, Rachelle Bienstock, Christopher Southan, Carolina H Andrade
The Zika virus (ZIKV) is a flavivirus of the family Flaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it either in vitro or in vivo...
2016: F1000Research
P Sneha, C George Priya Doss
The pace of anti-diabetic drug discovery is very slow in spite of increasing rate of prevalence of Type 2 Diabetes which remains a major public health concern. Though extensive research steps are taken in the past decade, yet craves for better of new treatment strategies to overcome the current scenario. One such general finding is the evolution of gliptins which discriminately inhibits DPP4 (Dipeptidyl peptidase-4) enzyme. Although the mechanism of action of gliptin is highly target oriented and accurate, still its long-term use stands unknown...
October 12, 2016: Life Sciences
Carlos Henrique Tomich de Paula da Silva, Carlton Anthony Taft
The knowledge of the bioactive conformation for an active hit is relevant because of the easier interpretation and the general quality of the recognition models of protein and ligand. With the aim of investigating potential bioactive conformations without previous structural knowledge of the molecular target, we present herewith a 'protocol' that could be used which includes generation of low-energy conformations, calculations of tridimensional descriptors and investigation of structural similarity via principal component analysis...
October 14, 2016: Journal of Biomolecular Structure & Dynamics
Nan Gao, Tao Liang, Yuan Yuan, Xiuchan Xiao, Yihuan Zhao, Yanzhi Guo, Menglong Li, Xuemei Pu
G-protein-coupled receptors (GPCRs) are important drug targets and generally activated by ligands. However, some experiments found that GPCRs also give rise to constitutive activity through some mutations (viz., CAM), which are usually associated with different kinds of diseases. However, the mechanisms of CAMs and their roles in interactions with drug-ligands are unclear in experiments. Herein, we used microsecond molecular dynamics simulations to study the effect of one important F282L mutation on β2AR in order to address the questions above...
October 13, 2016: Physical Chemistry Chemical Physics: PCCP
Jing Du, Martin Neuenschwander, Yong Yu, J Henry M Däbritz, Nina-Rosa Neuendorff, Kolja Schleich, Aitomi Bittner, Maja Milanovic, Gregor Beuster, Silke Radetzki, Edgar Specker, Maurice Reimann, Frank Rosenbauer, Stephan Mathas, Philipp Lohneis, Michael Hummel, Bernd Dörken, Jens Peter von Kries, Soyoung Lee, Clemens A Schmitt
Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling...
October 12, 2016: Blood
Saghi Sepehri, Lotfollah Saghaie, Afshin Fassihi
The fusion of viral and host cell membranes is mediated using gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. As the HIV-1 enters the host cells, the two helical regions (HR1 and HR2) in the ectodomain of gp41 form a six-helix bundle, which carries the target and viral cell membranes to close proximity. Steps of this process serve as attractive targets for developing HIV-1 fusion inhibitors. Identification of some novel HIV fusion inhibitors with the goal of blocking the formation of the six-helix bundle was accomplished by computer-aided drug design techniques...
October 12, 2016: Molecular Informatics
Maheswata Sahoo, Lingaraja Jena, Sangeeta Daf, Satish Kumar
Zika virus (ZIKV) is a mosquito borne pathogen, belongs to Flaviviridae family having a positive-sense single-stranded RNA genome, currently known for causing large epidemics in Brazil. Its infection can cause microcephaly, a serious birth defect during pregnancy. The recent outbreak of ZIKV in February 2016 in Brazil realized it as a major health risk, demands an enhanced surveillance and a need to develop novel drugs against ZIKV. Amodiaquine, prochlorperazine, quinacrine, and berberine are few promising drugs approved by Food and Drug Administration against dengue virus which also belong to Flaviviridae family...
September 2016: Genomics & Informatics
Jamil Al-Asri, Gyöngyi Gyémánt, Erika Fazekas, Gábor Lehoczki, Matthias F Melzig, Gerhard Wolber, Jérémie Mortier
Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme...
October 11, 2016: ChemMedChem
Wei-Lin Chen, Zhi-Hui Wang, Tao-Tao Feng, Dong-Dong Li, Chu-Hui Wang, Xiao-Li Xu, Xiao-Jin Zhang, Qi-Dong You, Xiao-Ke Guo
Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized...
September 30, 2016: Bioorganic & Medicinal Chemistry
W Geoffrey Wright, Jane McDevitt, Ryan Tierney, F Jay Haran, Kwadwo Osei Appiah-Kubi, Alex Dumont
PURPOSE: Balance impairment is a common sensorimotor symptom in mild traumatic brain injury (mTBI). We designed an affordable, portable virtual reality (VR)-based balance screening device (Virtual Environment TBI Screen [VETS]), which will be validated relative to the Neurocom Sensory Organization Test (SOT) to determine if it can replace commonly used postural assessments. METHODS: This preliminary study examines healthy adults (n = 56) and adults with mTBI (n = 11)...
October 10, 2016: Disability and Rehabilitation
Ahmed Taha Ayoub, Rabab M Abou El-Magd, Jack Xiao, Cody Wayne Lewis, Tatiana Tilli, Kenji Arakawa, Yosi Nindita, Gordon Chan, Luxin Sun, J N Mark Glover, Mariusz Klobukowski, Jack A Tuszynski
Lankacidin group antibiotics show strong antimicrobial activity against various Gram-positive bacteria. In addition, they were shown to have considerable antitumor activity against certain cell line models. For decades, the antitumor activity of lankacidin was associated with the mechanism of its antimicrobial action, that is interference with peptide bond formation during protein synthesis. This, however, was never confirmed experimentally. Due to significant similarity to paclitaxel-like hits in a previous computational virtual screening study, we suggested that the cytotoxic effect of lankacidin is due to a paclitaxel-like action...
October 8, 2016: Journal of Medicinal Chemistry
Nicolas Levoin, Olivier Labeeuw, Xavier Billot, Thierry Calmels, Denis Danvy, Stéphane Krief, Isabelle Berrebi-Bertrand, Jeanne-Marie Lecomte, Jean-Charles Schwartz, Marc Capet
The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds. The virtual screening was planed as a two-steps process. First, using a "scout screening" methodology, we have experimentally probed the H4R ligand binding site using a small size chemical library with very diverse structures, and identified a hit that further assist us in refining a raw 3D homology model...
September 24, 2016: European Journal of Medicinal Chemistry
Jinyan Li, Simon Fong, Shirley Siu, Sabah Mohammed, Jinan Fiaidhi, Kelvin K L Wong
Drug design involves classification of protein binding which is usually done in a computer simulation prior to extensive actual tests. Accurate classification of protein binding is essential but it is obstructed with a very challenging task of feature selection (FS) because there are too many potential features. Dorothea as a case of virtual screening in drug design, has 100,000 features that inflate to a very huge (of size 2(100,000) possible candidate feature subsets to be selected) but very sparse search space...
September 30, 2016: Computerized Medical Imaging and Graphics: the Official Journal of the Computerized Medical Imaging Society
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