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https://www.readbyqxmd.com/read/27911825/elucidating-the-druggable-interface-of-protein-protein-interactions-using-fragment-docking-and-coevolutionary-analysis
#1
Fang Bai, Faruck Morcos, Ryan R Cheng, Hualiang Jiang, José N Onuchic
Protein-protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein-protein interfaces...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27908829/exploring-the-binding-mechanism-of-heteroaryldihydropyrimidines-and-hepatitis-b-virus-capsid-combined-3d-qsar-and-molecular-dynamics
#2
Jing Tu, Jiao Jiao Li, Zhi Jie Shan, Hong Lin Zhai
The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects, in which heteroaryldihydropyrimidines (HAPs) have been identified as effective inhibitors of HBV capsid. In this paper, the binding mechanism of HAPs targeting on HBV capsid protein was explored through three-dimensional quantitative structure-activity relationship, molecular dynamics and binding free energy decompositions. The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV...
November 28, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27906178/a-mechanism-for-overcoming-p-glycoprotein-mediated-drug-resistance-novel-combination-therapy-that-releases-stored-doxorubicin-from-lysosomes-via-lysosomal-permeabilization-using-dp44mt-or-dpc
#3
Nicole A Seebacher, Des R Richardson, Patric J Jansson
The intracellular distribution of a drug can cause significant variability in both activity and selectivity. Herein, we investigate the mechanism by which the anti-cancer agents, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and the clinically trialed, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), re-instate the efficacy of doxorubicin (DOX), in drug-resistant P-glycoprotein (Pgp)-expressing cells. Both Dp44mT and DpC potently target and kill Pgp-expressing tumors, while DOX effectively kills non-Pgp-expressing cancers...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27903217/rational-drug-discovery-of-hcv-helicase-inhibitor-improved-docking-accuracy-with-multiple-seedings-of-autodock-vina-and-in-situ-minimization
#4
SeeKhai Lim, Rozana Othman, Rohana Yusof, ChoonHan Heh
BACKGROUND: Hepatitis C is a significant cause for end-stage liver diseases and liver transplantation which affects approximate 3% of the global populations. Despite the present of several direct antiviral agents in the treatment of hepatitis C, the standard treatment for HCV is accompanied by several drawbacks such as adverse side effects, high pricing of medications and the rapid emerging rate of resistant HCV variants. OBJECTIVES: To discover potential inhibitors for HCV helicase through an optimized in silico approach...
November 30, 2016: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/27900374/spatially-resolved-microfluidic-stimulation-of-lymphoid-tissue-ex-vivo
#5
Ashley E Ross, Maura C Belanger, Jacob F Woodroof, Rebecca R Pompano
The lymph node is a structurally complex organ of the immune system, whose dynamic cellular arrangements are thought to control much of human health. Currently, no methods exist to precisely stimulate substructures within the lymph node or analyze local stimulus-response behaviors, making it difficult to rationally design therapies for inflammatory disease. Here we describe a novel integration of live lymph node slices with a microfluidic system for local stimulation. Slices maintained the cellular organization of the lymph node while making its core experimentally accessible...
November 30, 2016: Analyst
https://www.readbyqxmd.com/read/27899832/development-and-application-of-a-stepwise-assessment-process-for-rational-redesign-of-sequential-skills-based-courses
#6
Casey E Gallimore, Andrea L Porter, Susanne G Barnett
Objective. To develop and apply a stepwise process to assess achievement of course learning objectives related to advanced pharmacy practice experiences (APPEs) preparedness and inform redesign of sequential skills-based courses. Design. Four steps comprised the assessment and redesign process: (1) identify skills critical for APPE preparedness; (2) utilize focus groups and course evaluations to determine student competence in skill performance; (3) apply course mapping to identify course deficits contributing to suboptimal skill performance; and (4) initiate course redesign to target exposed deficits...
October 25, 2016: American Journal of Pharmaceutical Education
https://www.readbyqxmd.com/read/27899145/bibliometric-analysis-of-publications-on-campylobacter-2000-2015
#7
Waleed M Sweileh, Samah W Al-Jabi, Ansam F Sawalha, Adham S AbuTaha, Sa'ed H Zyoud
BACKGROUND: Campylobacter species are widespread zoonotic pathogens. Campylobacter jejuni causes a form of gastroenteritis called campylobacteriosis. Campylobacter drug resistance is considered a serious threat. In order to better understand national and international research output on Campylobacter, we conducted this bibliometric overview of publications on Campylobacter. This study can be used to assess extent of interaction and response of researchers, food regulators, and health policy makers to global burden of campylobacateriosis...
November 29, 2016: Journal of Health, Population, and Nutrition
https://www.readbyqxmd.com/read/27897366/active-site-crowding-of-p450-3a4-as-a-strategy-to-alter-its-selectivity
#8
Paolo Schiavini, Kin J Cheong, Nicolas Moitessier, Karine Auclair
Substrate promiscuous enzymes are a promising starting point for the development of versatile biocatalysts. In this study, human cytochrome P450 3A4, known for its ability to metabolize hundreds of drugs, was engineered to alter its regio- and stereoselectivity. Rational mutagenesis was used to specifically introduce steric hindrance in the large active site of P450 3A4 and favour oxidation at a more sterically accessible position on the substrate. Hydroxylation of a synthetic precursor of (R)-lisofylline, a compound under investigation for its anti-inflammatory properties, was chosen as a first proof-of-principle application of our protein engineering strategy...
November 29, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27897114/ureas-applications-in-drug-design-and-development
#9
Ajit Dhananjay Jagtap, Nagendra Bharatrao Kondekar, Amit A Sadani, Ji-Wang Chern
The unique hydrogen binding capabilities of ureas make them an important functional group to make drug-target interactions and thus incorporated in small molecules displaying broad range of bioactivities. The related research and numerous excellent achievements of ureas applicability in drug design for the modulation of selectivity, stability, toxicity and pharmacokinetic profile of lead molecules have become active topic. This review aims to provide insights in to the significance of urea in drug design by summarizing successful studies of various urea derivatives as modulators biological targets (viz...
November 29, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27892723/optimization-and-stratification-of-multiple-sclerosis-treatment-in-fast-developing-economic-countries-a-perspective-from-qatar
#10
Dirk Deleu, Boulenouar Mesraoua, Hisham El Khider, Beatriz Canibano, Gayane Melikyan, Hassan Al Hail, Noha Mhjob, Anjushri Bhagat, Faiza Ibrahim, Yolande Hanssens
OBJECTIVE: The introduction of disease-modifying therapies (DMTs) - with varying degrees of efficacy for reducing annual relapse rate and disability progression - has considerably transformed the therapeutic landscape of relapsing-remitting multiple sclerosis (RRMS). We aim to develop rational evidence-based treatment recommendations and algorithms for the management of clinically isolated syndrome (CIS) and RRMS conform to the healthcare system in a fast-developing economic country such as Qatar...
November 28, 2016: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/27891677/staurosporine-scaffold-based-rational-discovery-of-the-wild-type-sparing-reversible-inhibitors-of-egfr-t790m-gatekeeper-mutant-in-lung-cancer-with-analog-sensitive-kinase-technology
#11
Xiaoyun Song, Xingcai Liu, Xi Ding
The human epidermal growth factor receptor (EGFR) has been established as an attractive target for lung cancer therapy. However, an acquired EGFR T790M gatekeeper mutation is frequently observed in patients treated with first-line anticancer agents such as gefitinib and erlotinib to cause drug resistance, largely limiting the application of small-molecule kinase inhibitors in EGFR-targeted chemotherapy. Previously, the reversible pan-kinase inhibitor staurosporine and its several analogs such as Gö6976 and K252a have been reported to selectively inhibit the EGFR T790M mutant (EGFR(T790M) ) over wild-type kinase (EGFR(WT) ), suggesting that the staurosporine scaffold is potentially to develop the wild-type sparing reversible inhibitors of EGFR(T790M) ...
November 28, 2016: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/27890784/identifying-residues-that-determine-scf-molecular-level-interactions-through-a-combination-of-experimental-and-in-silico-analyses
#12
Eitan Rabinovich, Michael Heyne, Anna Bakhman, Mickey Kosloff, Julia M Shifman, Niv Papo
The stem cell factor (SCF)/c-Kit receptor tyrosine kinase complex - with its significant roles in hematopoiesis and angiogenesis - is an attractive target for rational drug design. There is thus a need to map, in detail, the SCF/c-Kit interaction sites and the mechanisms that modulate this interaction. While most residues in the direct SCF/c-Kit binding interface can be identified from the existing crystal structure of the complex, other residues that affect binding through protein unfolding, intermolecular interactions, or allosteric or long-distance electrostatic effects cannot be directly inferred...
November 24, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27883944/allocative-and-implementation-efficiency-in-hiv-prevention-and-treatment-for-people-who-inject-drugs
#13
Clemens Benedikt, Sherrie L Kelly, David Wilson, David P Wilson
BACKGROUND: Estimated global new HIV infections among people who inject drugs (PWID) remained stable over the 2010-2015 period and the target of a 50% reduction over this period was missed. To achieve the 2020 UNAIDS target of reducing adult HIV infections by 75% compared to 2010, accelerated action in scaling up HIV programs for PWID is required. In a context of diminishing external support to HIV programs in countries where most HIV-affected PWID live, it is essential that available resources are allocated and used as efficiently as possible...
November 21, 2016: International Journal on Drug Policy
https://www.readbyqxmd.com/read/27881431/predictive-approaches-for-drug-combination-discovery-in-cancer
#14
Seyed Ali Madani Tonekaboni, Laleh Soltan Ghoraie, Venkata Satya Kumar Manem, Benjamin Haibe-Kains
Drug combinations have been proposed as a promising therapeutic strategy to overcome drug resistance and improve efficacy of monotherapy regimens in cancer. This strategy aims at targeting multiple components of this complex disease. Despite the increasing number of drug combinations in use, many of them were empirically found in the clinic, and the molecular mechanisms underlying these drug combinations are often unclear. These challenges call for rational, systematic approaches for drug combination discovery...
November 22, 2016: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/27874172/development-of-crizotinib-a-rationally-designed-tyrosine-kinase-inhibitor-for-non-small-cell-lung-cancer
#15
REVIEW
Candice C Poon, John J Kelly
Non-small cell lung cancer (NSCLC) is the number one cause of global mortality. Despite aggressive treatment, the prognosis is dismal. Patients with advanced NSCLC have a median survival of four months from the time of diagnosis. Fortunately, molecularly-based approaches to drug discovery have yielded a tyrosine kinase inhibitor, crizotinib, which significantly prolongs median progression free survival in a subset of patients. Although initial clinical trial results demonstrate crizotinib has a promising role to play in NSCLC treatment, development of resistance leaves much to be elucidated about how to effectively combat this deadly disease...
November 22, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27873118/current-update-of-a-carboxymethylcellulose-peg-conjugate-platform-for-delivery-of-insoluble-cytotoxic-agents-to-tumors
#16
Yang Yang, Joseph Bteich, Shyh-Dar Li
Cytotoxic chemotherapeutic agents are used as the standard therapy for a range of significant cancers, but many of these drugs suffer from poor water solubility and low selectivity, limiting their clinical efficacy. To overcome these shortcomings, Cellax™ drug delivery platform was developed. Cellax™ is a polymer-based nanoparticle drug delivery system designed to solubilize hydrophobic drugs and target them to solid tumors, thereby enhancing the efficacy and reducing the side effects. Cellax-docetaxel (Cellax-DTX) displayed improved pharmacokinetic, safety, and efficacy profiles compared to native DTX (Taxotere®) and Nab-paclitaxel (Nab-PTX, Abraxane®) in multiple animal models...
November 21, 2016: AAPS Journal
https://www.readbyqxmd.com/read/27872070/estimation-of-the-in-vivo-minimum-inhibitory-concentration-of-cipargamin-in-uncomplicated-plasmodium-falciparum-malaria
#17
Hien Tinh Tran, Nicholas J White, Thuy-Nhien Thanh Nguyen, Hoa Thi Nhu, Thuan Duc Phung, Joel Tarning, François Nosten, Baldur Magnusson, Jay Prakash Jain, Kamal Hamed
The minimum inhibitory concentration (MIC) of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure cure of malaria the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate polymerase chain reaction quantitation of low-density malaria parasitemia enables prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects, and now allows identification of the in-vivo MIC...
November 21, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27864679/prescription-of-antimalarial-drugs-in-the-pediatric-ward-of-the-national-hospital-of-lamord%C3%A3-in-niamey
#18
A Soumana, M Kamaye, B Issofou, H Dima, B Daouda, O N'Diaye, G Sall
In Niger, malaria is a major public health problem, due to the high number of deaths that are attributable to it and because of its heavy weight and socioeconomic status. The objective of this study was to contribute to the inventory of medical practices to rationalize the use of medicines and minimize the resistance phenomenon. This is a prospective study, which took place from May 1 to July 31, 2009, in the pediatric ward of the National Hospital of Lamordé. It concerned children aged from 0 to 14 years hospitalized and having received one or more antimalarial drugs during at least 24 h...
November 18, 2016: Bulletin de la Société de Pathologie Exotique
https://www.readbyqxmd.com/read/27863671/oral-transmucosal-delivery-of-naratriptan
#19
Mohammed Sattar, Majella E Lane
Naratriptan (NAR) is currently used as the hydrochloride salt (NAR.HCl) for the treatment of migraine and is available in tablet dosage forms for oral administration. Buccal drug delivery offers a number of advantages compared with conventional oral delivery including rapid absorption, avoidance of first pass metabolism and improved patient compliance. We have previously prepared and characterised the base form of NAR and shown that it has more favourable properties for buccal delivery compared with NAR.HCl...
November 30, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27862980/using-decision-modeling-to-guide-drug-allocation-during-a-shortage
#20
Heidi V Russell, M Brooke Bernhardt, Stacey Berg
BACKGROUND: Drug shortages require clinical teams to decide how to allocate drugs in limited supply among their patients. Ethical frameworks are invaluable for promoting rational approaches to drug distribution, but gaps remain between ethical theory and clinical application. The goal of this work was to explore how decision modeling could supplement ethical frameworks to inform drug distribution from the perspective of a clinical team. PROCEDURE: We created a hypothetical pediatric oncology clinic with a limited supply of 50,000 mg of methotrexate (MTX) and 21 patients due for treatment on one of six regimens...
November 15, 2016: Pediatric Blood & Cancer
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