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https://www.readbyqxmd.com/read/28743094/a-personalized-medicine-approach-to-the-design-of-dry-powder-inhalers-selecting-the-optimal-amount-of-bypass
#1
Thomas Kopsch, Darragh Murnane, Digby Symons
In dry powder inhalers (DPIs) the patient's inhalation manoeuvre strongly influences the release of drug. Drug release from a DPI may also be influenced by the size of any air bypass incorporated in the device. If the amount of bypass is high less air flows through the entrainment geometry and the release rate is lower. In this study we propose to reduce the intra- and inter-patient variations of drug release by controlling the amount of air bypass in a DPI. A fast computational method is proposed that can predict how much bypass is needed for a specified drug delivery rate for a particular patient...
July 22, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28743089/understanding-the-interaction-of-concanavalin-a-with-mannosyl-glycoliposomes-a-surface-plasmon-resonance-and-fluorescence-study
#2
Catalina Sandoval-Altamirano, Susana A Sanchez, Nancy F Ferreyra, German Gunther
The specificity of carbohydrate-protein interaction is a key factor in many biological processes and it is the foundation of technologies using glycoliposomes in drug delivery. The incorporation of glycolipids in vesicles is expected to increase their specificity toward particular targets such as lectins; however, the degree of exposure of the carbohydrate moiety at the liposome surface is a crucial parameter to be considered in the interaction. Herein we report the synthesis of mannose derivatives with one or two hydrophobic chains of different length, designed with the purpose of modifying the degree of exposure of the mannose when they were incorporated into liposomes...
July 18, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28743078/metabolite-identification-of-azd8055-in-sprague-dawley-rats-after-a-single-oral-administration-using-ultra-performance-liquid-chromatography-and-mass-spectrometry
#3
Md Mamunur Rashid, Hyun-A Oh, Hyunbeom Lee, Byung Hwa Jung
AZD8055 is an ATP-competitive specific dual mTOR inhibitor and exhibited potent antitumor activity on several types of solid tumors. However, the metabolism of AZD8055 in the body still remains unknown. In this study, metabolite identification of AZD8055 was performed using ultra high-performance liquid chromatography-ion trap mass spectrometry (UHPLC-IT-MS) through both in vitro and in vivo approaches using rat liver microsomes (RLMs) and rat plasma, urine and feces, respectively. A total of eight putative metabolites (five phase I and three phase II) were identified, and a tentative metabolic pathway was suggested for the first time...
July 8, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28743071/prediction-of-protein-structural-class-for-low-similarity-sequences-using-chou-s-pseudo-amino-acid-composition-and-wavelet-denoising
#4
Bin Yu, Lifeng Lou, Shan Li, Yusen Zhang, Wenying Qiu, Xue Wu, Minghui Wang, Baoguang Tian
Prediction of protein structural class plays an important role in protein structure and function analysis, drug design and many other biological applications. Prediction of protein structural class for low-similarity sequences is still a challenging task. Based on the theory of wavelet denoising, this paper presents a novel method of prediction of protein structural class for the first time. Firstly, the features of the protein sequence are extracted by using Chou's pseudo amino acid composition (PseAAC). Then the extracted feature information is denoised by two-dimensional (2D) wavelet...
July 14, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28742644/update-on-sglt2-inhibitors-new-data-released-at-the-american-diabetes-association
#5
Sara Lee
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are one of the newer classes of antiglycemic agents approved for the management of patients with type 2 diabetes mellitus. Due to their unique mechanism of action, SGLT2 inhibitors have shown to be beneficial beyond glucose control. The improvement in cardiovascular (CV) outcomes was first observed in the landmark EMPA-REG OUTCOMES study. Following these results, numerous CV outcome trials were designed to identify whether the beneficial CV and renal effects observed with empagliflozin are unique or a drug class effect...
September 2017: Critical Pathways in Cardiology
https://www.readbyqxmd.com/read/28742512/the-sphingomyelin-synthase-family-proteins-diseases-and-inhibitors
#6
Yang Chen, Yu Cao
Sphingomyelin (SM) is among the most important biomolecules in eukaryotes and acts as both constructive components and signal carrier in physiological process. SM is catalyzed by a membrane protein family, sphingomyelin synthases (SMSs), consisting of three members, SMS1, SMS2 and SMSr. SMSs modulate sphingomyelin and other sphingolipids levels, thereby regulating membrane mobility, ceramide-dependent apoptosis and DAG-dependent signaling pathway. SMSs was found associated with various diseases. Downregulation of SMS2 activity results in protective effects against obesity, atherosclerosis, and diabetes, makes SMS2 inhibitors potential medicines...
July 26, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28742416/comparisons-of-alcohol-and-drug-dependence-in-terms-of-attachments-and-clinical-issues
#7
Dana Zeid, Joshua Carter, Marc A Lindberg
BACKGROUND: Alcohol and drug dependencies are associated with different social stigmas, and some studies suggest they might exhibit different clinical presentations. Further, the treatments for each vary considerably. Alcohol versus drug use problems were compared in terms of attachment patterns and related clinical treatment issues in two interlocking studies using converging logic and designs. METHODS: In Study 1, alcohol versus drug dependence was defined in terms of a known groups design...
July 25, 2017: Substance Use & Misuse
https://www.readbyqxmd.com/read/28742266/p-coumaric-acid-a-dietary-polyphenol-ameliorates-inflammation-and-curtails-cartilage-and-bone-erosion-in-the-rheumatoid-arthritis-rat-model
#8
Manoj Kumar Neog, Samuel Joshua Pragasam, Moorthy Krishnan, Mahaboobkhan Rasool
This study was designed to explore the underlying mechanism of p-coumaric acid (CA), a dietary polyphenol in adjuvant-induced arthritis (AIA) rat model with reference to synovitis and osteoclastogenesis. Celecoxib (COX-2 selective inhibitor) (5 mg/kg b.wt) was used as a reference drug. CA remarkably suppressed the paw edema, body weight loss and inflammatory cytokine and chemokine levels (TNF-α, IL-1β, IL-6, and MCP-1) in serum and ankle joint of arthritic rats. Consistently, CA reduced the expression of osteoclastogenic factors (RANKL and TRAP), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17), and inflammatory enzymes (iNOS and COX-2) in arthritic rats...
July 25, 2017: BioFactors
https://www.readbyqxmd.com/read/28742140/short-16-mer-locked-nucleic-acid-splice-switching-oligonucleotides-restore-dystrophin-production-in-duchenne-muscular-dystrophy-myotubes
#9
Vanessa Borges Pires, Ricardo Simões, Kamel Mamchaoui, Célia Carvalho, Maria Carmo-Fonseca
Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28742068/a-peptide-based-viral-inactivator-inhibits-zika-virus-infection-in-pregnant-mice-and-fetuses
#10
Yufeng Yu, Yong-Qiang Deng, Peng Zou, Qian Wang, Yanyan Dai, Fei Yu, Lanying Du, Na-Na Zhang, Min Tian, Jia-Nan Hao, Yu Meng, Yuan Li, Xiaohui Zhou, Jasper Fuk-Woo Chan, Kwok-Yung Yuen, Cheng-Feng Qin, Shibo Jiang, Lu Lu
Zika virus (ZIKV), a re-emerging flavivirus associated with neurological disorders, has spread rapidly to more than 70 countries and territories. However, no specific vaccines or antiviral drugs are currently available to prevent or treat ZIKV infection. Here we report that a synthetic peptide derived from the stem region of ZIKV envelope protein, designated Z2, potently inhibits infection of ZIKV and other flaviviruses in vitro. We show that Z2 interacts with ZIKV surface protein and disrupts the integrity of the viral membrane...
July 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28741926/redesigned-spider-peptide-with-improved-antimicrobial-and-anticancer-properties
#11
Sonia Troeira Henriques, Nicole Lawrence, Stephanie Chaousis, Anjaneya S Ravipati, Olivier Cheneval, Aurélie H Benfield, Alysha G Elliott, Angela Maria Kavanagh, Matthew A Cooper, Lai Yue Chan, Yen-Hua Huang, David J Craik
Gomesin, a disulfide-rich antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against melanoma cells. In a recent study, a backbone cyclized analogue of gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic gomesin, understanding its selectivity towards melanoma cells and elucidating its antimicrobial and anticancer mode of action...
July 25, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28741876/discovery-of-novel-potent-muscarinic-m3-receptor-antagonists-with-proper-plasma-stability-by-structural-recombination-of-marketed-m3-antagonists
#12
Zuojuan Xiang, Jun Liu, Hongbin Sun, Xiaoan Wen
The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki =0...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741456/effects-of-oral-and-non-insulin-injectable-antidiabetic-treatment-in-hypertension-a-systematic-review
#13
Vasiliki Katsi, Georgios Georgiopoulos, Georgia Vogiatzi, Dimitrios Oikonomou, Maria Megapanou, John Skoumas, Charalampos Vlachopoulos, Petros Nihoyannopoulos, Dimitris Tousoulis
BACKGROUND: Diabetes mellitus type 2 (T2DM) often co-exists with hypertension, and this aggregation of co-morbidities amplifies the risk for future cardiovascular events. Therefore, it appears crucial to understand the essence of choosing oral and non-insulin injectable anti-diabetic drugs (ADs) with a favorable hemodynamic impact that could partially attenuate the increased baseline cardiovascular risk. OBJECTIVE: We sought to evaluate the effect of ADs on blood pressure (BP) indices and to assess the potential role of certain ADs towards hypertension treatment...
May 19, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28741245/the-last-frontier-transcatheter-devices-for-percutaneous-or-minimally-invasive-treatment-of-chronic-heart-failure
#14
REVIEW
V J Nijenhuis, L Sanchis, J A S van der Heyden, P Klein, B J W M Rensing, A Latib, F Maisano, J M Ten Berg, P Agostoni, M J Swaans
Heart failure has a high prevalence in the general population. Morbidity and mortality of heart failure patients remain high, despite improvements in drug therapy, implantable cardioverter-defibrillators and cardiac resynchronisation therapy. New transcatheter implantable devices have been developed to improve the treatment of heart failure. There has been a rapid development of minimally invasive or transcatheter devices used in the treatment of heart failure associated with aortic and mitral valve disease and these devices are being incorporated into routine clinical practice at a fast rate...
July 24, 2017: Netherlands Heart Journal
https://www.readbyqxmd.com/read/28741125/identification-of-carboxylate-phosphate-and-phenoxide-functionalities-in-deprotonated-molecules-related-to-drug-metabolites-via-ion-molecule-reactions-with-water-and-diethylhydroxyborane
#15
Hanyu Zhu, Xin Ma, John Y Kong, Minli Zhang, Hilkka I Kenttämaa
Tandem mass spectrometry based on ion-molecule reactions has emerged as a powerful tool for structural elucidation of ionized analytes. However, most currently used reagents were designed to react with protonated analytes, making them suboptimal for acidic analytes that are preferentially detected in negative ion mode. In this work we demonstrate that the phenoxide, carboxylate, and phosphate functionalities can be identified in deprotonated molecules by use of a combination of two reagents, diethylmethoxyborane (DEMB) and water...
July 24, 2017: Journal of the American Society for Mass Spectrometry
https://www.readbyqxmd.com/read/28741112/investigation-of-naphthofuran-moiety-as-potential-dual-inhibitor-against-bace-1-and-gsk-3%C3%AE-molecular-dynamics-simulations-binding-energy-and-network-analysis-to-identify-first-in-class-dual-inhibitors-against-alzheimer-s-disease
#16
Akhil Kumar, Gaurava Srivastava, Swati Srivastava, Seema Verma, Arvind S Negi, Ashok Sharma
BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches...
August 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28741044/efficacy-and-tolerability-of-asenapine-compared-with-olanzapine-in-borderline-personality-disorder-an-open-label-randomized-controlled-trial
#17
Paola Bozzatello, Paola Rocca, Maria Uscinska, Silvio Bellino
BACKGROUND: Asenapine is a new second-generation antipsychotic that is understudied in borderline personality disorder (BPD). Only one study investigating the use of the drug in this indication (an open-label pilot study) has been conducted to date. OBJECTIVE: The present open-label, randomized, controlled trial aimed to evaluate the efficacy and tolerability of asenapine in comparison with olanzapine, the most broadly studied antipsychotic in BPD. METHODS: A total of 51 outpatients aged between 18 and 50 years with a diagnosis of BPD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were assigned for 12 weeks to asenapine (5-10 mg/day) or olanzapine (5-10 mg/day)...
July 24, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28740622/drug-pricing-and-reimbursement-information-management-processes-and-decision-making-in-the-global-economy
#18
Dimitrios Tsourougiannis
Background: Cost-containment initiatives are re-shaping the pharmaceutical business environment and affecting market access as well as pricing and reimbursement decisions. Effective price management procedures are too complex to accomplish manually. Prior to February 2013, price management within Astellas Pharma Europe Ltd was done manually using an Excel database. The system was labour intensive, slow to update, and prone to error. An innovative web-based pricing information management system was developed to address the shortcomings of the previous system...
2017: Journal of Market Access & Health Policy
https://www.readbyqxmd.com/read/28740608/gne-886-a-potent-and-selective-inhibitor-of-the-cat-eye-syndrome-chromosome-region-candidate-2-bromodomain-cecr2
#19
Terry D Crawford, James E Audia, Steve Bellon, Daniel J Burdick, Archana Bommi-Reddy, Alexandre Côté, Richard T Cummings, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, Hariharan Jayaram, Ying Jiang, Shivangi Joshi, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Arianne Neiss, Eneida Pardo, F Anthony Romero, Peter Sandy, Robert J Sims, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Yongyun Wang, Zhaowu Xu, Laura Zawadzke, Xiaoqin Zhu, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound...
July 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28740606/structure-guided-strategy-for-the-development-of-potent-bivalent-erk-inhibitors
#20
Bernhard C Lechtenberg, Peter D Mace, E Hampton Sessions, Robert Williamson, Romain Stalder, Yann Wallez, Gregory P Roth, Stefan J Riedl, Elena B Pasquale
ERK is the effector kinase of the RAS-RAF-MEK-ERK signaling cascade, which promotes cell transformation and malignancy in many cancers and is thus a major drug target in oncology. Kinase inhibitors targeting RAF or MEK are already used for the treatment of certain cancers, such as melanoma. Although the initial response to these drugs can be dramatic, development of drug resistance is a major challenge, even with combination therapies targeting both RAF and MEK. Importantly, most resistance mechanisms still rely on activation of the downstream effector kinase ERK, making it a promising target for drug development efforts...
July 13, 2017: ACS Medicinal Chemistry Letters
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