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https://www.readbyqxmd.com/read/27907876/rational-design-and-synthesis-of-1-5-disubstituted-tetrazoles-as-potent-inhibitors-of-the-mdm2-p53-interaction
#1
Ewa Surmiak, Constantinos G Neochoritis, Bogdan Musielak, Aleksandra Twarda-Clapa, Katarzyna Kurpiewska, Grzegorz Dubin, Carlos Camacho, Tad A Holak, Alexander Dömling
Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.
November 16, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27905582/regarding-the-torsional-flexibility-of-the-dihydrolipoic-acid-s-pharmacophore-1-3-propanedithiol
#2
Annalisa Vigorito, Camilla Calabrese, Ettore Paltanin, Sonia Melandri, Assimo Maris
The conformational space of antioxidant dihydrolipoic acid has been explored through the investigation of its pharmacophore, 1,3-propanedithiol. Five of the possible 25 non-equivalent isomers (namely: gGGg', gGGg, g'AGg, gAGg and g'AGg') were observed in the 59.6-74.4 GHz frequency region using free-jet absorption rotational spectroscopy. Furthermore, for three of them, the (34)S mono-substituted isotopologues were also detected in natural abundance. Theoretical simulations show that the balance of steric and electronic intramolecular interactions arises on a shallow conformational potential energy surface and suggest that in polar solvents the flexibility of the dithiol chain is greater than that in the isolated phase...
December 1, 2016: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/27903755/homobivalent-conjugation-increases-the-allosteric-effect-of-9-aminoacridine-at-the-%C3%AE-1-adrenergic-receptors
#3
Adrian P Campbell, Laurence P G Wakelin, William A Denny, Angela M Finch
The α1 adrenergic receptors are targets for a number of cardiovascular and CNS conditions, however current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1 adrenergic ligands, yet there is little information describing this drug class at the α1 adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α1A and α1B adrenergic receptors...
November 30, 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27903422/novel-butyrylcholinesterase-inhibitors-through-pharmacophore-modeling-virtual-screening-and-dft-based-approaches-along-with-design-of-bioisosterism-based-analogues
#4
Dhrubajyoti Gogoi, Amrita Kashyap Chaliha, Diganta Sarma, Bibhuti Bhusan Kakoti, Alak Kumar Buragohain
Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration...
November 27, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27900730/understanding-the-interactions-of-high-mobility-group-of-protein-domain-b1-with-dna-adducts-generated-by-platinum-anticancer-molecules-using-in-silico-approaches
#5
Gauri Misra, Shipra Gupta, Neetu Jabalia
Platinum coordination compounds having cis geometry are frequently prescribed for various types of cancers. Protein dysregulation is one of the major factors contributing towards cancer metastasis. Head and neck squamous cell carcinoma (HNSCC) is one of the cancers where platinum-based compounds are used either alone or in combination with radiation as therapy. The underlying interactions of these compounds with both DNA and proteins are crucial for the drug response. The compounds forms DNA adducts which are recognized by conserved, non-chromosomal high-mobility group box 1 (HMGB1) proteins...
November 30, 2016: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/27898710/identification-of-a-novel-inhibitory-allosteric-site-in-p38%C3%AE
#6
Patricia Gomez-Gutierrez, Pedro M Campos, Miguel Vega, Juan J Perez
In the present study, we report the discovery of a novel allosteric inhibitory site for p38α, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38α-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38α. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38α is phosphorylated or not...
2016: PloS One
https://www.readbyqxmd.com/read/27894776/design-synthesis-cyclooxygenase-inhibition-and-biological-evaluation-of-new-1-3-5-triaryl-4-5-dihydro-1h-pyrazole-derivatives-possessing-amino-methanesulfonyl-pharmacophore
#7
Khaled R A Abdellatif, Wael A A Fadaly
A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole 10a-l was designed and synthesized via cyclization of chalcones 8a-f with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9a-b. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives (10a, 10b, 10g and 10h) were the most potent derivatives (ED50=55...
November 21, 2016: Bioorganic Chemistry
https://www.readbyqxmd.com/read/27892459/borane-catalysed-ring-opening-and-closing-cascades-of-furans-leading-to-silicon-functionalized-synthetic-intermediates
#8
Chinmoy K Hazra, Narasimhulu Gandhamsetty, Sehoon Park, Sukbok Chang
The conversion of renewable biomass resources to synthetically valuable chemicals is highly desirable, but remains a formidable challenge in regards to the substrate scope and reaction conditions. Here we present the development of tris(pentafluorophenyl)borane-catalysed conversion of furans via ring-opening and closing cascade processes to afford silicon-functionalized synthetic chemicals under transition metal-free conditions. The furan ring-opening with hydrosilanes is highly efficient (TON up to 2,000) and atom-economical without forming any byproduct to give rise to α-silyloxy-(Z)-alkenyl silanes...
November 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27889632/synthesis-biological-evaluation-and-in-silico-molecular-modeling-of-pyrrolyl-benzohydrazide-derivatives-as-enoyl-acp-reductase-inhibitors
#9
Shrinivas D Joshi, Sheshagiri R Dixit, Venkatarao H Kulkarni, Christian Lherbet, Mallikarjuna N Nadagouda, Tejraj M Aminabhavi
In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD(+) that fitted well within the binding pocket of InhA...
November 17, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27889206/protlid-a-residue-based-pharmacophore-approach-to-identify-cognate-protein-ligands-in-the-immunoglobulin-superfamily
#10
Eng-Hui Yap, Andras Fiser
Members of the extracellular immunoglobulin superfamily (IgSF) play a key role in immune regulation through the control of the co-stimulatory pathway, and have emerged as potent drug targets in cancers, infectious diseases, and autoimmunity. Despite the difficult experimental access to this class of proteins, single structures of ectodomains of IgSF proteins are solved with regularity. However, the most biologically critical challenge for this class of proteins is the identification of their cognate ligands that communicate intercellular signals...
November 11, 2016: Structure
https://www.readbyqxmd.com/read/27881652/inhibition-of-human-cytomegalovirus-pul89-terminase-subunit-blocks-virus-replication-and-genome-cleavage
#11
Yan Wang, Lili Mao, Jayakanth Kankanala, Zhengqiang Wang, Robert J Geraghty
: Human cytomegalovirus terminase complex cleaves the concatemeric genomic DNA into unit lengths during genome packaging and particle assembly. This process is an attractive drug target because cleavage of concatemeric DNA is not required in mammalian cell DNA replication, indicating that drugs targeting the terminase complex could be safe and selective. One component of the human cytomegalovirus terminase complex, pUL89, provides the endonucleolytic activity for genome cleavage and the domain responsible is reported to have an RNase H-like fold...
November 23, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27865910/multi-target-directed-therapeutic-potential-of-7-methoxytacrine-adamantylamine-heterodimers-in-the-alzheimer-s-disease-treatment
#12
Zuzana Gazova, Ondrej Soukup, Vendula Sepsova, Katarina Siposova, Lucie Drtinova, Petr Jost, Katarina Spilovska, Jan Korabecny, Eugenie Nepovimova, Diana Fedunova, Martin Horak, Martina Kaniakova, Ze-Jun Wang, Ayman K Hamouda, Kamil Kuca
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory...
November 16, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27863747/symmetrical-aryl-linked-bis-iminothiazolidinones-as-new-chemical-entities-for-the-inhibition-of-monoamine-oxidases-synthesis-in-vitro-biological-evaluation-and-molecular-modelling-analysis
#13
Naeem Abbas, Sumera Zaib, Syeda Mahwish Bakht, Aliya Ibrar, Imtiaz Khan, Sadaf Batool, Aamer Saeed, Jamshed Iqbal
The multifactorial nature of Parkinson's disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives (3a-g and 5a-e) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N'-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature...
November 9, 2016: Bioorganic Chemistry
https://www.readbyqxmd.com/read/27862213/synthesis-and-preliminary-biological-evaluation-of-a-99m-tc-chlorambucil-derivative-as-a-potential-tumor-imaging-agent
#14
Jianguo Lin, Ling Qiu, Gaochao Lv, Ke Li, Wei Wang, Guiqing Liu, Xueyu Zhao, Shanshan Wang
Technetium-99 m-based radiopharmaceuticals have been used widely as diagnostic agents in the nuclear medicine. Chlorambucil (CLB) as one typical alkylating drug exhibits excellent inhibition effects against many human malignancies. In order to develop and explore a novel potential imaging agent for early diagnosis of tumors, tricarbonyl technetium-99 m and rhenium complexes based on the tridentate ligand dipicolylamine (DPA) bound to the chlorambucil pharmacophore were designed and synthesized: (99m) Tc-DPA-CLB (3) and Re-DPA-CLB (4)...
November 16, 2016: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/27853354/development-of-novel-her2-inhibitors-against-gastric-cancer-derived-from-flavonoid-source-of-syzygium-alternifolium-through-molecular-dynamics-and-pharmacophore-based-screening
#15
Tirumalasetty Muni Chandra Babu, Aluru Rammohan, Vijaya Bhaskar Baki, Savita Devi, Duvvuru Gunasekar, Wudayagiri Rajendra
Continuous usage of synthetic chemotherapeutic drugs causes adverse effects, which prompted for the development of alternative therapeutics for gastric cancer from natural source. This study was carried out with a specific aim to screen gastroprotective compounds from the fruits of Syzygium alternifolium (Myrtaceae). Three flavonoids, namely, 1) 5-hydroxy-7,4'-dimethoxy-6,8-di-C-methylflavone, 2) kaempferol-3-O-β-d-glucopyranoside, and 3) kaempferol-3-O-α-l-rhamnopyranoside were isolated from the above medicinal plant by employing silica gel column chromatography and are characterized by NMR techniques...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27844505/conformer-and-pharmacophore-based-identification-of-peptidomimetic-inhibitors-of-chikungunya-virus-nsp2-protease
#16
Sonali Dhindwal, Pooja Kesari, Harvijay Singh, Pravindra Kumar, Shailly Tomar
Chikungunya virus nsP2 replication protein is a cysteine protease, which cleaves the nonstructural nsP1234 polyprotein into functional replication components. The cleavage and processing of nsP1234 by nsP2 protease is essential for the replication and proliferation of the virus. Thus, ChikV nsP2 protease is a promising target for antiviral drug discovery. In this study, the crystal structure of the C-terminal domain of ChikV nsP2 protease (PDB ID: 4ZTB) was used for structure based identification and rational designing of peptidomimetic inhibitors against nsP2 protease...
December 2, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27843298/endoperoxide-antimalarials-development-structural-diversity-and-pharmacodynamic-aspects-with-reference-to-1-2-4-trioxane-based-structural-scaffold
#17
REVIEW
Mithun Rudrapal, Dipak Chetia
Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27842893/identification-of-novel-fluorescent-probes-preventing-prp-sc-replication-in-prion-diseases
#18
Ludovica Zaccagnini, Simone Brogi, Margherita Brindisi, Sandra Gemma, Giulia Chemi, Giuseppe Legname, Giuseppe Campiani, Stefania Butini
Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrP(Sc) that represents the pathological variant of the normally folded cellular protein PrP(C). Molecules that bind the cellular isoform PrP(C) preventing its misfolding, could arrest the progression of pathological conditions related to the abnormal PrP protein. In this context, by combining 3D-QSAR model, derived from pharmacophore-based alignment, with molecular docking procedures and physico-chemical properties prediction we have developed a virtual screening protocol to find novel chemicals able to prevent PrP(C) misfolding...
November 1, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27835744/analysis-of-positions-and-substituents-on-genotoxicity-of-fluoroquinolones-with-quantitative-structure-activity-relationship-and-3d-pharmacophore-model
#19
Chen Fengxian, Hai Reti
The genotoxicity values of 21 quinolones were studied to establish a quantitative structure-activity relationship model and 3D Pharmacophore model separately for screening essential positions and substituents that contribute to genotoxicity of fluoroquinolones (FQs). A full factor experimental design was performed to analyze the specific main effect and second-order interaction effect of different positions and substituents on genotoxicity, forming a reasonable modification scheme which was validated on typical FQ with genotoxicity and efficacy data...
November 8, 2016: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/27834131/recent-highlights-on-molecular-hybrids-potentially-useful-in-central-nervous-system-disorders
#20
Mariana Matias, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
Molecular hybridization is a recent strategy based in the covalent fusion of two or more existing pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides, such as enkephalins, deltorphin and endomorphin, have been developed and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control...
November 11, 2016: Mini Reviews in Medicinal Chemistry
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