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https://www.readbyqxmd.com/read/27914361/development-of-cxcr4-modulators-by-virtual-hts-of-a-novel-amide-sulfamide-compound-library
#1
Renren Bai, Qi Shi, Zhongxing Liang, Younghyoun Yoon, Yiran Han, Amber Feng, Shuangping Liu, Yoonhyeun Oum, C Chris Yun, Hyunsuk Shim
CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign...
November 24, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914299/the-effects-of-fluorine-substitution-on-the-chemical-properties-and-inhibitory-capacity-of-donepezil-anti-alzheimer-drug-density-functional-theory-and-molecular-docking-calculations
#2
Azita Khosravan, Safora Marani, Mohammad Sadegh Sadeghi Googheri
Drug fluorination has the potential to reproduce useful drugs with decreasing the side effect of them. Identifying the effect of this improvement on the chemical properties and biological interactions of drug symbolizes a meaningful progress in drug design. Here the fluorination of Donepezil as an anti-Alzheimer drug, including 7 fluorinated derivatives of it, was investigated computationally. In the first part of our calculations, the most important chemical properties of drug that affects the drug efficiency were investigated by applying the M06/6-31g (d, p) and M062X/6-31g (d, p) levels of theories...
November 25, 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/27914279/identification-and-quantification-of-4-methylethcathinone-4-mec-and-3-4-methylenedioxypyrovalerone-mdpv-in-hair-by-lc-ms-ms-after-chronic-administration
#3
Jean Claude Alvarez, Isabelle Etting, Emuri Abe, Antoine Villa, Nicolas Fabresse
4-Methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV) are synthetic cathinones. The objective of this study was to develop a method in order to measure these compounds in hair of a patient. After decontamination, 20mg of hair were grinded and incubated in phosphate buffer pH 5.0 in presence of 100ng of MDMA-d5 used as internal standard. Double basic liquid-liquid extraction was performed. Samples were separated on a 1.9μm Hypersil GOLD PFP column (100×2.1mm) using gradient elution. Compounds were detected by a LCQ TSQ Vantage XP triple-quadrupole mass spectrometer...
November 24, 2016: Forensic Science International
https://www.readbyqxmd.com/read/27914066/computational-tools-for-allosteric-drug-discovery-site-identification-and-focus-library-design
#4
Wenkang Huang, Ruth Nussinov, Jian Zhang
Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914063/episweep-computationally-driven-reengineering-of-therapeutic-proteins-to-reduce-immunogenicity-while-maintaining-function
#5
Yoonjoo Choi, Deeptak Verma, Karl E Griswold, Chris Bailey-Kellogg
Therapeutic proteins are yielding ever more advanced and efficacious new drugs, but the biological origins of these highly effective therapeutics render them subject to immune surveillance within the patient's body. When recognized by the immune system as a foreign agent, protein drugs elicit a coordinated response that can manifest a range of clinical complications including rapid drug clearance, loss of functionality and efficacy, delayed infusion-like allergic reactions, more serious anaphylactic shock, and even induced auto-immunity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914058/osprey-predicts-resistance-mutations-using-positive-and-negative-computational-protein-design
#6
Adegoke Ojewole, Anna Lowegard, Pablo Gainza, Stephanie M Reeve, Ivelin Georgiev, Amy C Anderson, Bruce R Donald
Drug resistance in protein targets is an increasingly common phenomenon that reduces the efficacy of both existing and new antibiotics. However, knowledge of future resistance mutations during pre-clinical phases of drug development would enable the design of novel antibiotics that are robust against not only known resistant mutants, but also against those that have not yet been clinically observed. Computational structure-based protein design (CSPD) is a transformative field that enables the prediction of protein sequences with desired biochemical properties such as binding affinity and specificity to a target...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914045/achievements-and-challenges-in-computational-protein-design
#7
Ilan Samish
Computational protein design (CPD), a yet evolving field, includes computer-aided engineering for partial or full de novo designs of proteins of interest. Designs are defined by a requested structure, function, or working environment. This chapter describes the birth and maturation of the field by presenting 101 CPD examples in a chronological order emphasizing achievements and pending challenges. Integrating these aspects presents the plethora of CPD approaches with the hope of providing a "CPD 101". These reflect on the broader structural bioinformatics and computational biophysics field and include: (1) integration of knowledge-based and energy-based methods, (2) hierarchical designated approach towards local, regional, and global motifs and the integration of high- and low-resolution design schemes that fit each such region, (3) systematic differential approaches towards different protein regions, (4) identification of key hot-spot residues and the relative effect of remote regions, (5) assessment of shape-complementarity, electrostatics and solvation effects, (6) integration of thermal plasticity and functional dynamics, (7) negative design, (8) systematic integration of experimental approaches, (9) objective cross-assessment of methods, and (10) successful ranking of potential designs...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914040/formulation-optimization-and-ex-vivo-and-in-vivo-evaluation-of-celecoxib-microemulsion-based-gel-for-transdermal-delivery
#8
Mengyuan Cao, Lili Ren, Guoguang Chen
Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, Smix, and water were confirmed by pseudo-ternary phase diagram studies and central composite design...
December 2, 2016: AAPS PharmSciTech
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#9
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
December 2, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27913974/incorporation-of-estradiol-benzoate-to-cidr-protocol-improves-the-reproductive-responses-in-crossbred-dairy-heifers
#10
Muhammad Usman Mehmood, Ahmad Qamar, Abdul Sattar, Liaquat Ahmad, Nasim Ahmad
The present study was designed to determine the effect of estradiol benzoate (EB) on reproductive response following a controlled internal drug release (CIDR) protocol in crossbred (Sahiwal × Friesian) dairy heifers. In the first trial, a total of 100 crossbred dairy heifers were treated with CIDR protocol for 7 days and injected with the PGF2α on day 6. After 24 h of CIDR removal, one group (EB = 50) was injected with estradiol benzoate whereas the other (control = 50) remained untreated. Estrus intensity and response were recorded visually and ovulation rate was recorded by ultrasonography...
December 2, 2016: Tropical Animal Health and Production
https://www.readbyqxmd.com/read/27913752/expression-and-bioactivity-of-human-alpha-fetoprotein-in-a-bac-to-bac-system
#11
Bo Lin, Kun Liu, Wenting Wang, Wei Li, Xu Dong, Yi Chen, Yan Lu, Junli Guo, Mingyue Zhu, Mengsen Li
Alpha-fetoprotein (AFP) is an early serum growth factor in fetal embryonic development and hepatic oncogenesis. A growing number of investigations of AFP as a tumor-specific biomarker have concluded that AFP is an important target for cancer treatment. AFP also plays an immunomodulatory role in the treatment of several autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, myasthenia gravis, and thyroiditis. In an effort to support biochemical screening and drug design and discovery, we attempted to express and purify human AFP in a Bac-to-Bac system...
December 2, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27913672/first-model-of-dimeric-lrrk2-the-challenge-of-unrevealing-the-structure-of-a-multidomain-parkinson-s-associated-protein
#12
REVIEW
Giambattista Guaitoli, Bernd K Gilsbach, Francesco Raimondi, Christian Johannes Gloeckner
Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of Mendelian forms of Parkinson's disease, among autosomal dominant cases. Its gene product, LRRK2, is a large multidomain protein that belongs to the Roco protein family exhibiting GTPase and kinase activity, with the latter activity increased by pathogenic mutations. To allow rational drug design against LRRK2 and to understand the cross-regulation of the G- and the kinase domain at a molecular level, it is key to solve the three-dimensional structure of the protein...
December 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27913493/novel-agents-in-follicular-lymphoma-choosing-the-best-target
#13
Laurie H Sehn
Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913115/computer-design-synthesis-and-bioactivity-analyses-of-drugs-like-fingolimod-used-in-the-treatment-of-multiple-sclerosis
#14
Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaattin Şen
Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis...
November 18, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27911825/elucidating-the-druggable-interface-of-protein-protein-interactions-using-fragment-docking-and-coevolutionary-analysis
#15
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/27911758/multimodal-imaging-for-dreadd-expressing-neurons-in-living-brain-and-their-application-to-implantation-of-ipsc-derived-neural-progenitors
#16
Bin Ji, Hiroyuki Kaneko, Takafumi Minamimoto, Haruhisa Inoue, Hiroki Takeuchi, Katsushi Kumata, Ming-Rong Zhang, Ichio Aoki, Chie Seki, Maiko Ono, Masaki Tokunaga, Satoshi Tsukamoto, Koji Tanabe, Ryong-Moon Shin, Takeharu Minamihisamatsu, Seiji Kito, Barry J Richmond, Tetsuya Suhara, Makoto Higuchi
: Chemogenetic manipulation of neuronal activities has been enabled by a designer receptor (designer receptor exclusively activated by designer drugs, DREADD) that is activated exclusively by clozapine-N-oxide (CNO). Here, we applied CNO as a functional reporter probe to positron emission tomography (PET) of DREADD in living brains. Mutant human M4 DREADD (hM4Di) expressed in transgenic (Tg) mouse neurons was visualized by PET with microdose [(11)C]CNO. Deactivation of DREADD-expressing neurons in these mice by nonradioactive CNO at a pharmacological dose could also be captured by arterial spin labeling MRI (ASL-MRI)...
November 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27911718/attacking-hiv-1-rna-versus-dna-by-sequence-specific-approaches-rnai-versus-crispr-cas
#17
REVIEW
Elena Herrera-Carrillo, Ben Berkhout
Human immunodeficiency virus type 1 (HIV-1) infection can be effectively controlled by potent antiviral drugs, but this never results in a cure. The patient should therefore take these drugs for the rest of his/her life, which can cause drug-resistance and adverse effects. Therefore, more durable therapeutic strategies should be considered, such as a stable gene therapy to protect the target T cells against HIV-1 infection. The development of potent therapeutic regimens based on the RNA interference (RNAi) and clustered regularly interspaced short palindromic repeats (CRISPR-Cas) mechanisms will be described, which can be delivered by lentiviral vectors...
October 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27911475/carboplatin-complexed-and-crgd-conjugated-unimolecular-nanoparticles-for-targeted-ovarian-cancer-therapy
#18
Yuyuan Wang, Liwei Wang, Guojun Chen, Shaoqin Gong
Platinum-based chemotherapy has been widely used to treat cancers including ovarian cancer; however, it suffers from dose-limiting toxicity. Judiciously designed drug nanocarriers can enhance the anticancer efficacy of platinum-based chemotherapy while reducing its systemic toxicity. Herein the authors report a stable and water-soluble unimolecular nanoparticle constructed from a hydrophilic multi-arm star block copolymer poly(amidoamine)-b-poly(aspartic acid)-b-poly(ethylene glycol) (PAMAM-PAsp-PEG) conjugated with both cRGD (cyclo(Arg-Gly-Asp-D-Phe-Cys) peptide and cyanine5 (Cy5) fluorescent dye as a platinum-based drug nanocarrier for targeted ovarian cancer therapy...
December 1, 2016: Macromolecular Bioscience
https://www.readbyqxmd.com/read/27911359/directed-protein-packaging-within-outer-membrane-vesicles-from-escherichia-coli-design-production-and-purification
#19
Nathan J Alves, Kendrick B Turner, Scott A Walper
An increasing interest in applying synthetic biology techniques to program outer membrane vesicles (OMV) are leading to some very interesting and unique applications for OMV where traditional nanoparticles are proving too difficult to synthesize. To date, all Gram-negative bacteria have been shown to produce OMV demonstrating packaging of a variety of cargo that includes small molecules, peptides, proteins and genetic material. Based on their diverse cargo, OMV are implicated in many biological processes ranging from cell-cell communication to gene transfer and delivery of virulence factors depending upon which bacteria are producing the OMV...
November 16, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27911037/decoding-the-molecular-basis-for-the-population-mechanism-of-the-triplet-phototoxic-precursors-in-uva-light-activated-pyrimidine-anticancer-drugs
#20
Lara Martínez-Fernández, Giovanni Granucci, Marvin Pollum, Carlos Crespo-Hernández, Maurizio Persico, Ines Corral Perez
Photosensitization of DNA by thionucleosides is a promising photo-chemotherapeutic treatment option for a variety of malignancies. DNA metabolization of thiated prodrugs can lead to cell death upon exposure to a low dose of UVA light. The exact mechanisms of thionucleoside phototoxicity are still not fully understood. In this work, we have combined femtosecond broadband transient absorption experiments with state-of-the-art molecular simulations to provide mechanistic insights for the ultrafast and efficient population of the triplet-state in the UVA-activated pyrimidine anticancer drug: 4-thiothymine...
December 2, 2016: Chemistry: a European Journal
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