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https://www.readbyqxmd.com/read/29147793/pharmacophoric-characteristics-of-dengue-virus-ns2b-ns3pro-inhibitors-a-systematic-review-of-the-most-promising-compounds
#1
REVIEW
Camyla Alves Leonel, William Gustavo Lima, Michelli Dos Santos, Ariane Coelho Ferraz, Alex Gutterres Taranto, José Carlos de Magalhães, Luciana Lara Dos Santos, Jaqueline Maria Siqueira Ferreira
Dengue virus (DENV) infection can lead to a wide range of clinical manifestations, including fatal hemorrhagic complications. There is a need to find effective pharmacotherapies to treat this disease due to the lack of specific immunotherapies and antiviral drugs. That said, the DENV NS2B/NS3pro protease complex is essential in both the viral multiplication cycle and in disease pathogenesis, and is considered a promising target for new antiviral therapies. Here, we performed a systematic review to evaluate the pharmacophoric characteristics of promising compounds against NS2B/NS3pro reported in the past 10 years...
November 16, 2017: Archives of Virology
https://www.readbyqxmd.com/read/29147502/chemical-space-guided-discovery-of-antimicrobial-bridged-bicyclic-peptides-against-pseudomonas-aeruginosa-and-its-biofilms
#2
Ivan Di Bonaventura, Xian Jin, Ricardo Visini, Daniel Probst, Sacha Javor, Bee-Ha Gan, Gaëlle Michaud, Antonino Natalello, Silvia Maria Doglia, Thilo Köhler, Christian van Delden, Achim Stocker, Tamis Darbre, Jean-Louis Reymond
Herein we report the discovery of antimicrobial bridged bicyclic peptides (AMBPs) active against Pseudomonas aeruginosa, a highly problematic Gram negative bacterium in the hospital environment. Two of these AMBPs show strong biofilm inhibition and dispersal activity and enhance the activity of polymyxin, currently a last resort antibiotic against which resistance is emerging. To discover our AMBPs we used the concept of chemical space, which is well known in the area of small molecule drug discovery, to define a small number of test compounds for synthesis and experimental evaluation...
October 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/29144742/successful-identification-of-cardiac-troponin-calcium-sensitizers-using-a-combination-of-virtual-screening-and-roc-analysis-of-known-troponin-c-binders
#3
Melanie L Aprahamian, Svetlana B Tikunova, Morgan V Price, Andres F Cuesta, Jonathan P Davis, Steffen Lindert
Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin. Calcium binds to the N-terminal domain of troponin C (cNTnC) which initiates the process of contraction. Heart failure is a consequence of a disruption of this process. With the prevalence of this condition, a strong need exists to find novel compounds to increase the calcium sensitivity of cNTnC. Desirable are small chemical molecules that bind to the interface between cTnC and the cTnI switch peptide and exhibit calcium sensitizing properties by possibly stabilizing cTnC in an open conformation...
November 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29140675/identification-of-novel-allosteric-modulators-of-glutamate-transporter-eaat2
#4
Sandhya Kortagere, Ole Valente Mortensen, Jingsheng Xia, William Lester, Yuhong Fang, Yellamelli V V Srikanth, Joseph M Salvino, Andreia Cristina Karklin Fontana
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsyand neurodegenerative diseases among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain...
November 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29138965/molecular-dynamics-and-integrated-pharmacophore-based-identification-of-dual-formula-see-text-inhibitors
#5
Maninder Kaur, Pankaj Kumar Singh, Manjinder Singh, Renu Bahadur, Om Silakari
Despite increase in the understanding of the pathogenesis of rheumatoid arthritis (RA), it remains a tough challenge. The advent of kinases involved in key intracellular pathways in pathogenesis of RA may provide a new phase of drug discovery for RA. The present study is aimed to identify dual JAK3/[Formula: see text] inhibitors by developing an optimum pharmacophore model integrating the information revealed by ligand-based pharmacophore models and structure-based pharmacophore models (SBPMs). For JAK3 inhibitors, the addition of an aromatic ring feature and for [Formula: see text] the addition of a hydrophobic feature proposed by SBPMs lead to five-point pharmacophore (i...
November 14, 2017: Molecular Diversity
https://www.readbyqxmd.com/read/29136525/improving-the-carbonic-anhydrase-inhibition-profile-of-the-sulfamoylphenyl-pharmacophore-by-attachment-of-carbohydrate-moieties
#6
Leonardo E Riafrecha, Silvia Bua, Claudiu T Supuran, Pedro A Colinas
One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated 'the sugar approach'. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C-glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes...
November 2, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29135926/proline-based-carbamates-as-cholinesterase-inhibitors
#7
Hana Pizova, Marketa Havelkova, Sarka Stepankova, Andrzej Bak, Tereza Kauerova, Violetta Kozik, Michal Oravec, Ales Imramovsky, Peter Kollar, Pavel Bobal, Josef Jampilek
Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46...
November 14, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29134510/drug-design-for-alk-positive-nsclc-an-integrated-pharmacophore-based-3d-qsar-and-virtual-screening-strategy
#8
Nivya James, V Shanthi, K Ramanathan
The increasing death rates related to anaplastic lymphoma kinase (ALK)-positive lung cancer culminated in a significant interest in the discovery of novel inhibitors for ALK. In the present research work, pharmacophore-based 3D QSAR modeling and virtual screening strategy have been carried out to address these issues. Initially, a five-point pharmacophore model was developed using the biological data of 50 compounds which includes an FDA-approved ALK inhibitor, crizotinib. Using the generated pharmacophore, a 3D QSAR model was developed and used as a query to screen the DrugBank database...
November 13, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/29133049/design-and-synthesis-of-novel-c14-urea-tetrandrine-derivatives-with-potent-anti-cancer-activity
#9
Junjie Lan, Lan Huang, Huayong Lou, Chao Chen, Tangjingjun Liu, Shengcao Hu, Yao Yao, Junrong Song, Jun Luo, Yazhou Liu, Bin Xia, Lei Xia, Xueyi Zeng, Yaacov Ben-David, Weidong Pan
Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9)...
November 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29133041/design-synthesis-and-biological-evaluation-of-novel-aryldiketo-acids-with-enhanced-antibacterial-activity-against-multidrug-resistant-bacterial-strains
#10
Ilija N Cvijetić, Tatjana Ž Verbić, Pedro Ernesto de Resende, Paul Stapleton, Simon Gibbons, Ivan O Juranić, Branko J Drakulić, Mire Zloh
Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29130688/from-classification-to-regression-multitasking-qsar-modeling-using-a-novel-modular-neural-network-simultaneous-prediction-of-anticonvulsant-activity-and-neurotoxicity-of-succinimides
#11
Davor Antanasijević, Jelena Antanasijević, Nemanja Trišović, Gordana Ušćumlić, Viktor Pocajt
Succinimides, which contain a pharmacophore responsible for anticonvulsant activity, are frequently used antiepileptic drugs and the synthesis of their new derivatives with improved efficacy and tolerability presents an important task. Nowadays, multitarget/tasking methodologies focused on quantitative-structure activity relationships (mt-QSAR/mtk-QSAR) have an important role in the rational design of drugs since they enable simultaneous prediction of several standard measures of biological activities at diverse experimental conditions and against different biological targets...
November 13, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29130358/gelatinase-inhibitors-a-patent-review-2011-2017
#12
Xun Li
Gelatinase represents a promising biotarget in new drug development as it is closely related to various pathological events, including but not limited to neoplasm, aging, respiratory and neurological disorders. Gelatinase inhibitors are thereby designated as chemotherapeutics or as mechanistic probe to figure out the unrecognized functions of MMP members. Areas covered: The focus of this article is to highlight recently issued patents concerning the naturally available or synthetic gelatinase inhibitors (2011-2017), where the chemical structures, SAR investigation, biological application...
November 12, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29130348/tryptophan-containing-non-cationizable-opioid-peptides-a-new-chemotype-with-unusual-structure-and-in-vivo-activity
#13
Rossella De Marco, Luca Gentilucci
Recently, a new family of opioid peptides containing tryptophan came to the spotlight for the absence of the fundamental protonable tyramine 'message' pharmacophore. Structure-activity relationship investigations led to diverse compounds, characterized by different selectivity profiles and agonist or antagonist effects. Substitution at the indole of Trp clearly impacted peripheral/central antinociceptivity. These peculiarities prompted to gather all the compounds in a new class, and to coin the definition 'Tryptophan-Containing Non-Cationizable Opioid Peptides', in short 'TryCoNCOPs'...
November 13, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29127011/rational-design-of-small-molecules-that-modulate-the-transcriptional-function-of-the-response-regulator-phop
#14
Xiaoyu Qing, Ami De Weerdt, Marc De Maeyer, Hans Steenackers, Arnout Voet
The response regulator PhoP, which is part of the PhoP/PhoQ two-component system, regulates the expression of multiple genes involved in controlling virulence in Salmonella enterica serovar Typhimurium and other species of Gram-negative bacteria. Modulating the phosphorylation-mediated dimerization in the receiver domain may interfere with the transcriptional function of PhoP. In this study, we analyzed the therapeutic potential of the PhoP receiver domain by exploring it as a potential target for drug design...
November 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29126725/conformationally-rigid-derivatives-of-way-267-464-synthesis-and-pharmacology-at-the-human-oxytocin-and-vasopressin-1a-receptors
#15
William T Jorgensen, Damien W Gulliver, Timothy A Katte, Eryn L Werry, Tristan A Reekie, Mark Connor, Michael Kassiou
WAY-267,464 (1) and twelve conformationally rigid analogues (3a-f-4a-f) were synthesised, characterised and evaluated in cellular assays with the aim of systematically exploring interactions with the oxytocin receptor (OTR). Each analogue was evaluated in radioligand binding displacement assays at both human OTR and arginine vasopressin 1a receptors (V1aR). Physiological characterisation was determined by whole cell IP1 accumulation assays on stably transfected human embryonic kidney (HEK) cells. Incorporation of the rigid, optionally substituted benzene ring abolished OTR activity and diminished V1aR pharmacology when compared to 1...
October 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29126724/dual-or-multi-targeting-inhibitors-the-next-generation-anticancer-agents
#16
REVIEW
Nulgumnalli Manjunathaiah Raghavendra, Divya Pingili, Sundeep Kadasi, Akhila Mettu, S V U M Prasad
Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. An increasing interest in this approach is indicated by a steady upsurge in the number of articles on targeting dual/multi proteins published in the last 5 years. Combining different inhibitors that destiny specific single target is the standard treatment for cancer. A new generation of dual or multi-targeting drugs is emerging, where a single chemical entity can act on multiple molecular targets...
October 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29115449/the-rational-search-for-pde10a-inhibitors-from-sophora%C3%A2-flavescens-roots-using-pharmacophore%C3%A2-and-docking%C3%A2-based-virtual-screening
#17
Han-Tian Fan, Jun-Fang Guo, Yu-Xin Zhang, Yu-Xi Gu, Zhong-Qi Ning, Yan-Jiang Qiao, Xing Wang
Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well‑known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors...
October 25, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29113495/pharmacophore-modelling-virtual-screening-and-molecular-docking-studies-on-pld1-inhibitors
#18
D K Behera, P M Behera, L Acharya, A Dixit
Lipid metabolism plays a significant role in influenza virus replication and subsequent infection. The regulatory mechanism governing lipid metabolism and viral replication is not properly understood to date, but both Phospholipase D (PLD1 and PLD2) activities are stimulated in viral infection. In vitro studies indicate that chemical inhibition of PLD1 delays viral entry and reduction of viral loads. The current study reports a three-dimensional pharmacophore model based on 35 known PLD1 inhibitors. A sub-set of 25 compounds was selected as the training set and the remaining 10 compounds were kept in the test set...
November 8, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29112287/synthesis-biological-evaluation-and-molecular-modeling-study-of-substituted-benzyl-benzamides-as-cetp-inhibitors
#19
Reema Abu Khalaf, Dima Sabbah, Eveen Al-Shalabi, Samar Bishtawi, Ghadeer Albadawi, Ghassan Abu Sheikha
Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82...
November 7, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29111525/crystallographic-studies-of-cinnamamide-derivatives-as-a-means-of-searching-for-anticonvulsant-activity
#20
Ewa Żesławska, Wojciech Nitek, Henryk Marona, Agnieszka Gunia-Krzyżak
A cinnamamide (3-phenylprop-2-enamide) core is present in many pharmacologically active compounds. We report three new crystal structures of N-substituted cinnamamide derivatives which were screened for anticonvulsant activity, namely (R,S)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide, C12H15NO2, (1), (R,S)-(2E)-N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide, C13H17NO2, (2), and (2E)-1-(4-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one, C14H17NO2, (3). Compounds (1) and (2) crystallize in the Pbca space group with one molecule in the asymmetric unit, whereas compound (3) crystallizes in the P21/c space group with two molecules in the asymmetric unit...
November 1, 2017: Acta Crystallographica. Section C, Structural Chemistry
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