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Computational drug design

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https://www.readbyqxmd.com/read/28806858/the-haemtrack-home-therapy-reporting-system-design-implementation-strengths-and-weaknesses-a-report-from-uk-haemophilia-centre-doctors-organisation
#1
C R M Hay, H Xiang, M Scott, P W Collins, R Liesner, G Dolan, R Hollingsworth
INTRODUCTION: Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. METHODS: The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones...
August 14, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28796192/computational-studies-on-acetylcholinesterases
#2
REVIEW
Yechun Xu, Shanmei Cheng, Joel L Sussman, Israel Silman, Hualiang Jiang
Functions of biomolecules, in particular enzymes, are usually modulated by structural fluctuations. This is especially the case in a gated diffusion-controlled reaction catalyzed by an enzyme such as acetylcholinesterase. The catalytic triad of acetylcholinesterase is located at the bottom of a long and narrow gorge, but it catalyzes the extremely rapid hydrolysis of the neurotransmitter, acetylcholine, with a reaction rate close to the diffusion-controlled limit. Computational modeling and simulation have produced considerable advances in exploring the dynamical and conformational properties of biomolecules, not only aiding in interpreting the experimental data, but also providing insights into the internal motions of the biomolecule at the atomic level...
August 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28795601/poly-glutamic-dendrimer-based-conjugates-for-cancer-vaccination-a-computational-design-for-targeted-delivery-of-antigens
#3
L I F Moura, N Martinho, L C Silva, T S Barata, S Brocchini, H F Florindo, M Zloh
Computational techniques are useful to predict interaction models and molecular properties for the design of drug delivery systems, such as dendrimers. This work evaluated the impact of surface modifications of mannosamine-conjugated multifunctional poly(glutamic acid) (PG)-dendrimers as nanocarriers of the tumour associated antigens (TAA) MART-1, gp100:44 and gp100:209. Molecular dynamics simulations and docking studies were performed. Nitrobenzoxadiazole (NBD)-PG-G4-dendrimer displayed 64 carboxylic groups, however, the Frontier Molecular Orbital Theory study evidenced that only 32 of those were available to form covalent bonds...
August 10, 2017: Journal of Drug Targeting
https://www.readbyqxmd.com/read/28791598/opioid-medications-in-the-management-of-chronic-abdominal-pain
#4
REVIEW
Dajie Wang
PURPOSE OF REVIEW: Chronic abdominal pain is a complex medical condition. The causes of chronic abdominal pain are extremely diverse ranging from chronic pancreatitis, Crohn's disease, to chronic pain with no clear etiology. Treatment of chronic abdominal pain remains a challenge in our clinical practice. While current interventions with celiac plexus blocks and pain medications provide some relief for these patients, but these treatments are typically less efficacious and limited by various adverse effects...
August 8, 2017: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/28780071/myotonic-dystrophy-candidate-small-molecule-therapeutics
#5
REVIEW
Piotr Konieczny, Estela Selma-Soriano, Anna S Rapisarda, Juan M Fernandez-Costa, Manuel Perez-Alonso, Ruben Artero
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences...
August 2, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28775266/in-silico-model-of-the-human-clc-kb-chloride-channel-pore-mapping-biostructural-pathology-and-drug-screening
#6
Maxime Louet, Sara Bitam, Naziha Bakouh, Yohan Bignon, Gabrielle Planelles, David Lagorce, Maria A Miteva, Dominique Eladari, Jacques Teulon, Bruno O Villoutreix
The human ClC-Kb channel plays a key role in exporting chloride ions from the cytosol and is known to be involved in Bartter syndrome type 3 when its permeation capacity is decreased. The ClC-Kb channel has been recently proposed as a potential therapeutic target to treat hypertension. In order to gain new insights into the sequence-structure-function relationships of this channel, to investigate possible impacts of amino-acid substitutions, and to design novel inhibitors, we first built a structural model of the human ClC-Kb channel using comparative modeling strategies...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28774731/potent-influenza-a-virus-entry-inhibitors-targeting-a-conserved-region-of-hemagglutinin
#7
Dongguo Lin, Yinzhu Luo, Guang Yang, Fangfang Li, Xiangkun Xie, Daiwei Chen, Lifang He, Jingyu Wang, Chunfeng Ye, Shengsheng Lu, Lin Lv, Shuwen Liu, Jian He
Influenza A viruses (IAVs) induce acute respiratory disease and cause significant morbidity and mortality throughout the world. With the emergence of drug-resistant viral strains, new and effective anti-IAV drugs with different modes of action are urgently needed. In this study, by conjugating cholesterol to the N-terminus of the short peptide KKWK, a lipopeptide named S-KKWK was created. The anti-IAV test indicated that S-KKWK and its derivatives displayed potent antiviral activities against a broad variety of influenza A viral strains including oseltamivir-resistant strains and clinically relevant isolates with IC50 values ranging from 0...
July 31, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28771551/computational-investigation-of-conformational-variability-and-allostery-in-cathepsin-k-and-other-related-peptidases
#8
Marko Novinec
Allosteric targeting is progressively gaining ground as a strategy in drug design. Its success, however, depends on our knowledge of the investigated system. In the case of the papain-like cysteine peptidase cathepsin K, a major obstacle in our understanding of allostery is represented by the lack of observable conformational change at the active site. This makes it difficult to understand how binding of effectors at known allosteric sites translates into modified enzyme activity. Herein, we address this issue by a computational approach based on experimental data...
2017: PloS One
https://www.readbyqxmd.com/read/28768772/a-computational-combinatorial-approach-identifies-a-protein-inhibitor-of-superoxide-dismutase-1-misfolding-aggregation-and-cytotoxicity
#9
Victor Banerjee, Ofek Oren, Efrat Ben-Zeev, Ran Taube, Stanislav Engel, Niv Papo
Molecular agents that specifically bind and neutralize misfolded and toxic superoxide dismutase 1 (SOD1) mutant proteins may find application in attenuating the disease progression of familial amyotrophic lateral sclerosis (fALS). However, high structural similarities between the wild-type and mutant SOD1 proteins limit the utility of this approach. Here, we addressed this challenge by converting a promiscuous natural human IgG binding domain, the hyperthermophilic variant of protein G (HTB1), into a highly specific aggregation inhibitor (designated HTB1M) of two fALS-linked SOD1 mutants, SOD1G93A and SOD1G85R...
August 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28766941/a-computational-investigation-of-small-molecule-engagement-of-hot-spots-at-protein-protein-interaction-interfaces
#10
David Xu, Yubing Si, Samy O Meroueh
The binding affinity of a protein-protein interaction is concentrated at amino acids known as hot spots. It has been suggested that small molecules disrupt protein-protein interactions by either (i) engaging receptor protein hot spots; or (ii) mimicking hot spots of the protein ligand. Yet, to date, no systematic studies have been done to explore how effectively existing small-molecule protein-protein interaction inhibitors mimic or engage hot spots at protein interfaces. Here, we employ explicit-solvent molecular dynamics simulations and end-point MM-GBSA free energy calculations to explore this question...
August 2, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28766108/a-pharmacoepidemiology-database-system-for-monitoring-risk-due-to-the-use-of-medicines-by-new-zealand-primary-care-patients
#11
Andrew M Tomlin, David M Reith, David J Woods, Hywel S Lloyd, Alesha Smith, John S Fountain, Murray W Tilyard
INTRODUCTION: The use of large record-linked healthcare databases for drug safety research and surveillance is now accepted practice. New Zealand's standardized national healthcare datasets provide the potential to automate the conduct of pharmacoepidemiological studies to provide rapid validation of medicine safety signals. OBJECTIVES: Our objectives were to describe the methodology undertaken by a semi-automated computer system developed to rapidly assess risk due to drug exposure in New Zealand's population of primary care patients and to compare results from three studies with previously published findings...
August 1, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/28766097/ranking-docking-poses-by-graph-matching-of-protein-ligand-interactions-lessons-learned-from-the-d3r-grand-challenge-2
#12
Priscila da Silva Figueiredo Celestino Gomes, Franck Da Silva, Guillaume Bret, Didier Rognan
A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method...
August 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28766075/protein-binding-hot-spots-prediction-from-sequence-only-by-a-new-ensemble-learning-method
#13
Shan-Shan Hu, Peng Chen, Bing Wang, Jinyan Li
Hot spots are interfacial core areas of binding proteins, which have been applied as targets in drug design. Experimental methods are costly in both time and expense to locate hot spot areas. Recently, in-silicon computational methods have been widely used for hot spot prediction through sequence or structure characterization. As the structural information of proteins is not always solved, and thus hot spot identification from amino acid sequences only is more useful for real-life applications. This work proposes a new sequence-based model that combines physicochemical features with the relative accessible surface area of amino acid sequences for hot spot prediction...
August 1, 2017: Amino Acids
https://www.readbyqxmd.com/read/28764869/intelligent-computational-model-for-classification-of-sub-golgi-protein-using-oversampling-and-fisher-feature-selection-methods
#14
Jamal Ahmad, Faisal Javed, Maqsood Hayat
Golgi is one of the core proteins of a cell, constitutes in both plants and animals, which is involved in protein synthesis. Golgi is responsible for receiving and processing the macromolecules and trafficking of newly processed protein to its intended destination. Dysfunction in Golgi protein is expected to cause many neurodegenerative and inherited diseases that may be cured well if they are detected effectively and timely. Golgi protein is categorized into two parts cis-Golgi and trans-Golgi. The identification of Golgi protein via direct method is very hard due to limited available recognized structures...
May 2017: Artificial Intelligence in Medicine
https://www.readbyqxmd.com/read/28764083/in-silico-and-in-vitro-inhibition-of-cytochrome-p450-3a-by-synthetic-stilbenoids
#15
Loai Basheer, Keren Schultz, Yelena Guttman, Zohar Kerem
Inhibition of cytochrome P450 3A4 (CYP3A4), the major drug metabolizing enzyme, by dietary compounds has recently attracted increased attention. Evaluating the potency of the many known inhibitory compounds is a tedious and time consuming task, yet it can be achieved using computing tools. Here, CDOCKER and Glide served to design model inhibitors in order to characterize molecular features of an inhibitor. Assessing nitro-stilbenoids, both approaches suggested nitrostilbene to be a weaker inhibitor of CYP3A4 than resveratrol, and stronger than dimethoxy-nitrostilbene...
December 15, 2017: Food Chemistry
https://www.readbyqxmd.com/read/28759991/in-silico-prediction-of-ligand-binding-energies-in-multiple-therapeutic-targets-and-diverse-ligand-sets-a-case-study-on-bace1-tyk2-hsp90-and-perk-proteins
#16
Elizabeth Hatcher Frush, Sivakumar Sekharan, Shahar Keinan
We present here the use of QM/MM LIE (Linear interaction energy) based binding free energy calculations that greatly improve the precision and accuracy of predicting experimental binding affinities, in comparison to most current binding free energy methodologies, while maintaining reasonable computational times. Calculations are done for four sets of ligand-protein complexes, chosen based on diversity of protein types and availability of experimental data, totaling 140 ligands binding to therapeutic protein targets BACE1, TYK2, HSP90 and PERK...
July 31, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28757583/chalcone-derivatives-promising-starting-points-for-drug-design
#17
REVIEW
Marcelo N Gomes, Eugene N Muratov, Maristela Pereira, Josana C Peixoto, Lucimar P Rosseto, Pedro V L Cravo, Carolina H Andrade, Bruno J Neves
Medicinal chemists continue to be fascinated by chalcone derivatives because of their simple chemistry, ease of hydrogen atom manipulation, straightforward synthesis, and a variety of promising biological activities. However, chalcones have still not garnered deserved attention, especially considering their high potential as chemical sources for designing and developing new effective drugs. In this review, we summarize current methodological developments towards the design and synthesis of new chalcone derivatives and state-of-the-art medicinal chemistry strategies (bioisosterism, molecular hybridization, and pro-drug design)...
July 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28756685/computer-aided-drug-design-time-to-play-with-novel-chemical-matter
#18
Xavier Barril
No abstract text is available yet for this article.
July 31, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28756658/polymers-for-3d-printing-and-customized-additive-manufacturing
#19
Samuel Clark Ligon, Robert Liska, Jürgen Stampfl, Matthias Gurr, Rolf Mülhaupt
Additive manufacturing (AM) alias 3D printing translates computer-aided design (CAD) virtual 3D models into physical objects. By digital slicing of CAD, 3D scan, or tomography data, AM builds objects layer by layer without the need for molds or machining. AM enables decentralized fabrication of customized objects on demand by exploiting digital information storage and retrieval via the Internet. The ongoing transition from rapid prototyping to rapid manufacturing prompts new challenges for mechanical engineers and materials scientists alike...
August 9, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28756335/computational-approaches-to-understand-the-adverse-drug-effect-on-potassium-sodium-and-calcium-channels-for-predicting-tdp-cardiac-arrhythmias
#20
Mohsen Sharifi
Ion channels play a crucial role in the cardiovascular system. Our understanding of cardiac ion channel function has improved since their first discoveries. The flow of potassium, sodium and calcium ions across cardiomyocytes is vital for regular cardiac rhythm. Blockage of these channels, delays cardiac repolarization or tend to shorten repolarization and may induce arrhythmia. Detection of drug risk by channel blockade is considered essential for drug regulators. Advanced computational models can be used as an early screen for torsadogenic potential in drug candidates...
July 8, 2017: Journal of Molecular Graphics & Modelling
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