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Computational drug design

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https://www.readbyqxmd.com/read/28549952/drug-target-interaction-prediction-using-ensemble-learning-and-dimensionality-reduction
#1
Ali Ezzat, Min Wu, Xiao-Li Li, Chee-Keong Kwoh
Experimental prediction of drug-target interactions is expensive, time-consuming and tedious. Fortunately, computational methods help narrow down the search space for interaction candidates to be further examined via wet-lab techniques. Nowadays, the number of attributes/features for drugs and targets, as well as the amount of their interactions, are increasing, making these computational methods inefficient or occasionally prohibitive. This motivates us to derive a reduced feature set for prediction. In addition, since ensemble learning techniques are widely used to improve the classification performance, it is also worthwhile to design an ensemble learning framework to enhance the performance for drug-target interaction prediction...
May 23, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28548833/structure-activity-relationship-for-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase
#2
Harshini Neelakantan, Hua-Yu Wang, Virginia Vance, Jonathan D Hommel, Stanton F McHardy, Stanley J Watowich
Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogs resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC50 ~1 μM) NNMT inhibition...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28534676/applications-of-raman-spectroscopy-in-biopharmaceutical-manufacturing-a-short-review
#3
Kevin Buckley, Alan G Ryder
The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein- and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc...
June 2017: Applied Spectroscopy
https://www.readbyqxmd.com/read/28533317/cardiovascular-toxicity-of-illicit-anabolic-androgenic-steroid-use
#4
Aaron L Baggish, Rory B Weiner, Gen Kanayama, James I Hudson, Michael T Lu, Udo Hoffmann, Harrison G Pope
BACKGROUND: Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood. METHODS: Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume)...
May 23, 2017: Circulation
https://www.readbyqxmd.com/read/28533225/multi-functional-effects-of-a-small-molecule-stat3-inhibitor-on-nash-and-hcc-in-mice
#5
Kwang Hwa Jung, Wonbeak Yoo, Heather L Stevenson, Dipti Deshpande, Hong Shen, Mihai Gagea, Suk-Young Yoo, Jing Wang, Thomas Kris Eckols, Uddalak Bharadwaj, David J Tweardy, Laura Beretta
The incidence of hepatocellular carcinoma (HCC) is increasing in the United States and liver cancer is the second leading cause of cancer-related mortality worldwide. Non-alcoholic steatohepatitis (NASH) is becoming an important risk for HCC and most patients with HCC have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat HCC in the context of NASH and cirrhosis are urgently needed. <br /><br />Experimental Design: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in HCC tumors...
May 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28530546/the-role-of-qsar-and-virtual-screening-studies-in-type-2-diabetes-drug-discovery
#6
Simone Q Pantaleão, Drielli G V Fujji, Vinícius G Maltarollo, Danielle da C Silva, Gustavo H G Trossini, Karen C Weber, Luis P B Scott, Kathia M Honorio
BACKGROUND: Due to the increasing number of diabetes cases worldwide, there is an international concern to provide even more effective treatments to control this condition. METHODS: This review brings together a selection of studies that helped to broaden the comprehension of various biological targets and associated mechanisms involved in type 2 diabetes mellitus. RESULTS: Such studies demonstrated that QSAR techniques and virtual screenings have been successfully employed in drug design projects...
May 22, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28530521/the-direct-cost-of-managing-a-rare-disease-assessing-medical-and-pharmacy-costs-associated-with-duchenne-muscular-dystrophy-in-the-united-states
#7
Sarah Thayer, Christopher Bell, Craig M McDonald
BACKGROUND: A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. OBJECTIVE: To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones...
June 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/28530330/-the-sherlock-system-clinical-and-logistic-pharmaceutical-services
#8
Roni Leibowitz, Shahar Aflalo, Ornit Cohen, Ahuva Lustig
BACKGROUND: The drug inventory in the hospital consumes a large part of the hospital's budget. Classic drug management is based on weekly visits of the pharmacist in the departments, writing an order and dispensing it. This method is wasteful in terms of sending a bulk of drugs that will not necessarily be utilized, and it is also inefficient in terms of human resources. The unit-dose method, which is more advanced, is based on filling out individual prescriptions for each of the inpatients in the department...
August 2016: Harefuah
https://www.readbyqxmd.com/read/28528671/voltage-gated-sodium-channel-pharmacology-insights-from-molecular-dynamics-simulations
#9
Rong Chen, Amanda Buyan, Ben Corry
Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28523384/the-need-for-restructuring-the-disordered-science-of-amorphous-drug-formulations
#10
REVIEW
Khadijah Edueng, Denny Mahlin, Christel A S Bergström
The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago...
May 18, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28520533/a-fully-automated-high-throughput-zebrafish-behavioral-ototoxicity-assay
#11
Douglas W Todd, Rohit C Philip, Maki Niihori, Ryan A Ringle, Kelsey R Coyle, Sobia F Zehri, Jordan A Mudery, Ross H Francis, Jeffrey J Rodriguez, Abraham Jacob
Zebrafish animal models lend themselves to behavioral assays that can facilitate rapid screening of ototoxic, otoprotective, and otoregenerative drugs. Structurally similar to human inner ear hair cells, the mechanosensory hair cells on their lateral line allow the zebrafish to sense water flow and orient head-to-current in a behavior called rheotaxis. This rheotaxis behavior deteriorates in a dose-dependent manner with increased exposure to the ototoxin cisplatin, thereby establishing itself as an excellent biomarker for anatomic damage to lateral line hair cells...
May 18, 2017: Zebrafish
https://www.readbyqxmd.com/read/28512025/synthesis-of-methanesulphonamido-benzimidazole-derivatives-as-gastro-sparing-antiinflammatory-agents-with-antioxidant-effect
#12
Ratika Sharma, Alka Bali, Bhim Bahadur Chaudhari
A series of 5-methanesulphonamido benzimidazole derivatives were designed by combining the structural features of clinically useful anti-inflammatory drugs (nimesulide and rofecoxib) and antiulcer drugs (lansoprazole, omeprazole, etc.) based on physicochemical and 3D similarity studies. The compounds were evaluated for their anti-inflammatory activity in carrageenan induced rat paw edema model taking rofecoxib and indomethacin as standard drugs. In vitro antioxidant activity of the compounds was assessed by potassium ferricyanide reducing power (PFRAP) assay...
May 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28511910/synthesis-and-biological-research-of-novel-azaacridine-derivatives-as-potent-dna-binding-ligands-and-topoisomerase-ii-inhibitors
#13
Dan Li, Zigao Yuan, Shaopeng Chen, Cunlong Zhang, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0...
May 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28510428/statistical-analysis-and-prediction-of-covalent-ligand-targeted-cysteine-residues
#14
Weilin Zhang, Jianfeng Pei, Luhua Lai
Targeted covalent compounds or drugs have good potency as they can bind to a specific target for a long time with low doses. Most currently known covalent ligands were discovered by chance or by modifying existing non-covalent compounds to make them covalently attached to a nearby reactive residue. Computational methods for novel covalent ligand binding prediction are highly demanded. We performed statistical analysis on protein complexes with covalent ligands attached to cysteine residues. We found that covalent modified cysteine residues have unique features compared to those not attached to covalent ligands, including lower pKa, higher exposure and higher ligand binding affinity...
May 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28508402/risk-factors-for-human-immunodeficiency-virus-among-blood-donors-in-cameroon-evidence-for-the-design-of-an-africa-specific-donor-history-questionnaire
#15
Claude T Tagny, Georges Nguefack-Tsague, Diderot Fopa, Celestin Ashu, Estel Tante, Pauline Ngo Balogog, Olivier Donfack, Dora Mbanya, Syria Laperche, Edward Murphy
BACKGROUND: In sub-Saharan Africa improving the deferral of at-risk blood donors would be a cost-effective approach to reducing transfusion-transmitted human immunodeficiency virus (HIV) infections. We performed a pilot case-control study to identify the risk factors for HIV infection and to develop an adapted donor history questionnaire (DHQ) for sub-Saharan Africa. STUDY DESIGN AND METHODS: We recruited 137 HIV-positive donors (cases) and 256 HIV-negative donors (controls) and gathered risk factor data using audio computer-assisted self-interview...
May 15, 2017: Transfusion
https://www.readbyqxmd.com/read/28508374/autodock-and-autodocktools-for-protein-ligand-docking-beta-site-amyloid-precursor-protein-cleaving-enzyme-1-bace1-as-a-case-study
#16
Nehme El-Hachem, Benjamin Haibe-Kains, Athar Khalil, Firas H Kobeissy, Georges Nemer
Computational docking and scoring techniques have revolutionized structural bioinformatics by providing unprecedented insights on key aspects of ligand-receptor interaction. Docking is used for optimizing known drugs and for identifying novel binders by predicting their binding mode and affinity. AutoDock and AutoDockTools are free of charge techniques that have been extensively cited in the literature as essential tools in structure-based drug design. Moreover, these methods are fast enough to permit virtual screening of ligand libraries containing tens of thousands of compounds...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28506066/de-novo-computational-design-for-development-of-a-peptide-ligand-oriented-to-vegfr-3-with-high-affinity-and-long-circulation
#17
Hong M Li, Zhi P Dong, Qi Y Wang, Li X Liu, Bing X Li, Xiao N Ma, Ming S Lin, Tao Lu, Yue Wang
The overexpression of VEGFR-3 is correlated with a worse prognosis in lung cancer and has been regarded as a rational target for specific drug delivery. Here, VEGFR-3 homing peptide library was efficiently established by computational design. Strong fluorescent signal of selected peptides were observed in A549 cells, but much weaker in other cells. The positive immunostaining overlapped with VEGFR-3 confirmed high affinity and selectivity of one novel peptide (CP-7). In addition, cell uptake of FITC-CP-7 peptide was significantly blocked by co-injection of excess CP-7 peptide...
May 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28504946/essential-protein-detection-by-random-walk-on-weighted-protein-protein-interaction-networks
#18
Bin Xu, Jihong Guan, Yang Wang, Zewei Wang
Essential proteins are critical to the development and survival of cells. Identification of essential proteins is helpful for understanding the minimal set of required genes in a living cell and for designing new drugs. To detect essential proteins, various computational methods have been proposed based on protein-protein interaction (PPI) networks. However, protein interaction data obtained by highthroughput experiments usually contain high false positives, which negatively impacts the accuracy of essential protein detection...
May 12, 2017: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/28503546/computational-tool-for-fast-in-silico-evaluation-of-herg-k-channel-affinity
#19
Giulia Chemi, Sandra Gemma, Giuseppe Campiani, Simone Brogi, Stefania Butini, Margherita Brindisi
The development of a novel comprehensive approach for the prediction of hERG activity is herein presented. Software Phase has been used to derive a 3D-QSAR model, employing as alignment rule a common pharmacophore built on a subset of 22 highly active compounds (threshold Ki: 50 nM) against hERG K(+) channel. Five features comprised the pharmacophore: two aromatic rings (R1 and R2), one hydrogen-bond acceptor (A), one hydrophobic site (H), and one positive ionizable function (P). The sequential 3D-QSAR model developed with a set of 421 compounds (randomly divided in training and test set) yielded a test set (Q(2)) = 0...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/28503119/targeting-hiv-1-envelope-proteins-using-a-fragment-discovery-all-atom-computational-algorithm
#20
Michael H Peters
INTRODUCTION: HIV viral envelope proteins are targets for small inhibitor molecules aimed at disrupting the cellular entry process. Potential peptide-class inhibitor molecules (rDNA drugs) have been previously identified, with mixed results, through biomimicry and phage display experimental methods. Here we describe a new approach based on computational fragment discovery. The method has the potential to not only optimize peptide binding affinity but also to rapidly produce alternative inhibitors against mutated strains...
April 2017: Current Enzyme Inhibition
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