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https://www.readbyqxmd.com/read/28734205/identification-of-mycobacterium-tuberculosis-enoyl-acyl-carrier-protein-reductase-inhibitors-a-combined-in-silico-and-in-vitro-analysis
#1
Mohsin Y Lone, Mohd Athar, Vivek K Gupta, Prakash C Jha
Mycobacterium tuberculosis (Mtb), had developed evolutionary changes in its genome to adapt for survival and thereby generated multi-drug resistant strains. However, novel drug targets that remained unchanged for their biochemical role has impressed the research community to target such proteins. The comprehensive analysis of multiple protein targets has influenced us to make a consensus structural rule exploited by pharmacophore and other allied techniques from a large repository of protein structures. In this pursuit, we made a retrospective analysis of pharmacophores mapped from the tuberculosis structural proteome and identified unique patterns that can be employed for the novel molecules design...
July 14, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28731684/the-binding-mode-of-n-hydroxyamidines-to-indoleamine-2-3-dioxygenase-1-ido1
#2
Ute Friederike Röhrig, Vincent Zoete, Olivier Michielin
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through a N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or nitrogen atoms. Here, we use quantum chemical calculations, docking, and QM/MM calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode...
July 21, 2017: Biochemistry
https://www.readbyqxmd.com/read/28729623/3d-qsar-studies-on-maslinic-acid-analogs-for-anticancer-activity-against-breast-cancer-cell-line-mcf-7
#3
Sarfaraz Alam, Feroz Khan
Global prevalence of breast cancer and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of field based 3D-QSAR model based on human breast cancer cell line MCF7 in vitro anticancer activity, which defines the molecular level understanding and regions of structure-activity relationship for triterpene maslinic acid and its analogs. The key features such as average shape, hydrophobic regions and electrostatic patterns of active compounds were mined and mapped to virtually screen potential analogs...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729227/computational-and-experimental-prediction-of-molecules-involved-in-the-anti-melanoma-action-of-berberine
#4
Bin Liu, Xiu-Qiong Fu, Ting Li, Tao Su, Hui Guo, Pei-Li Zhu, Anfernee Kai-Wing Tse, Shi-Ming Liu, Zhi-Ling Yu
ETHNOPHARMACOLOGIC RELEVANCE: Berberine (BBR) is a naturally occurring alkaloid compound that can be found in Chinese medicinal herbs such as Rhizoma Coptidis and Phellodendri Cortex. These BBR containing herbs are commonly used by Chinese medicine doctors to treat cancers including melanoma. In this study, we explored proteins potentially involved in the anti-melanoma effects of BBR using an integrative computational and experimental approach. MATERIALS AND METHODS: Target proteins of BBR were predicted using the reverse pharmacophore screening, molecular docking and molecular dynamics...
July 17, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28728107/developing-potential-agents-against-atherosclerosis-design-synthesis-and-pharmacological-evaluation-of-novel-dual-inhibitors-of-oxidative-stress-and-squalene-synthase-activity
#5
Maria G Katselou, Alexios N Matralis, Angeliki P Kourounakis
For the treatment of multifactorial and complex diseases, it has become increasingly apparent that compounds acting at multiple targets often deliver superior efficacy compared to compounds with high specificity for only a single target. Based on previous studies demonstrating the important antioxidant and anti-hyperlipidemic effect of morpholine and 1,4-benzo(x/thi)azine derivatives (A-E), we hereby present the design, synthesis and pharmacological evaluation of novel dual-acting molecules as a therapeutic approach for atherosclerosis...
June 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28723234/flexible-small-molecular-anti-estrogens-with-n-n-dialkylated-2-5-diethoxy-4-morpholinoaniline-scaffold-targets-multiple-estrogen-receptor-conformations
#6
Bethany K Asare, Emmanuel Yawson, Rajendram V Rajnarayanan
Estrogen mediates various cellular processes including cell proliferation, differentiation, growth and mammary gland function. Estrogen Receptors (ERs) are expressed in 70% of breast cancers. Consequently, estrogen mediated ER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment. Estrogen Receptors are ligand-triggered transcription factors. However, in the absence of a cognate estrogenic ligand, ERs can be activated by a variety of other extracellular signals. Tamoxifen, an anti-estrogen that selectively targets ER, induces substantial regression of breast tumors and an increase in disease-free survival...
July 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28723092/microwave-assisted-synthesis-of-diversely-substituted-quinoline-based-dihydropyridopyrimidine-and-dihydropyrazolopyridine-hybrids
#7
Daniel Insuasty, Rodrigo Abonia, Braulio Insuasty, Jairo Quiroga, Kenneth K Laali, Manuel Nogueras, Justo Cobo
An efficient, catalyst-free and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro-1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products...
July 19, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28722479/oxindole-based-syk-and-jak3-dual-inhibitors-for-rheumatoid-arthritis-designing-synthesis-and-biological-evaluation
#8
Maninder Kaur, Manjinder Singh, Om Silakari
AIM: Autoimmune disorders have complex pathophysiology and focus is laid on the development of multitargeted agents. Two well-established kinases: SYK and JAK3, were considered to design dual inhibitors as potential therapeutics using various molecular-modeling approaches. Mehodology: Pharmacophore models for SYK and JAK3 were generated using oxindole-based inhibitors. Furthermore, an in-house database was designed that was screened against the best selected models. The obtained hits were employed for docking analysis and subjected to MM-GBSA analysis and molecular dynamic simulation...
July 19, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28722471/simulated-annealing-molecular-dynamics-and-ligand-receptor-contacts-analysis-for-pharmacophore-modeling
#9
Ma'mon M Hatmal, Mutasem O Taha
AIM: Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous. METHODOLOGY: This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Ligand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development...
July 19, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28720503/discovery-of-3-morpholino-imidazole-1-5-a-pyrazine-btk-inhibitors-for-rheumatoid-arthritis
#10
Sobhana Babu Boga, Abdul-Basit Alhassan, Jian Liu, Deodial Guiadeen, Arto Krikorian, Xiaolei Gao, James Wang, Younong Yu, Rajan Anand, Shilan Liu, Chundao Yang, Hao Wu, Jiaqiang Cai, Hugh Zhu, Jagdish Desai, Kevin Maloney, Ying-Duo Gao, Thierry O Fischmann, Jeremy Presland, My Mansueto, Zangwei Xu, Erica Leccese, Ian Knemeyer, Charles G Garlisi, Nathan Bays, Peter Stivers, Philip E Brandish, Alexandra Hicks, Alan Cooper, Ronald M Kim, Joseph A Kozlowski
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles...
March 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28720328/design-synthesis-molecular-modeling-and-anti-hyperglycemic-evaluation-of-quinazolin-4-3h-one-derivatives-as-potential-ppar%C3%AE-and-sur-agonists
#11
Mohamed K Ibrahim, Ibrahim H Eissa, Mohamed S Alesawy, Ahmed M Metwaly, Mohamed M Radwan, Mahmoud A ElSohly
Peroxisome proliferator-activated receptor gamma (PPARγ) and sulfonylurea receptor (SUR) play crucial roles in management of type-2 diabetes mellitus. In this study, a series of novel quinazoline-4(3H)-one-sulfonylurea hybrids were designed and synthesized as dual PPARγ and SUR agonists. The synthesized compounds were evaluated for their in vivo anti-hyperglycemic activities against STZ-induced hyperglycemic rats. Four compounds (19a, 19d, 19f and 25g) demonstrated potent activities with reduction in blood glucose levels of 40...
July 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28715203/a-bioinorganic-approach-to-fragment-based-drug-discovery-targeting-metalloenzymes
#12
Seth M Cohen
Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign...
July 17, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28715181/structural-insights-into-selective-ligand-receptor-interactions-leading-to-receptor-inactivation-utilizing-selective-melanocortin-3-receptor-antagonists
#13
Minying Cai, Udaya Kiran Marelli, Blake Mertz, Johannes G Beck, Florian Opperer, Florian Rechenmacher, Horst Kessler, Victor J Hruby
Systematic N-methylated derivatives of the melanocortin receptor ligand, SHU9119, lead to mul-tiple binding and functional selectivity towards melanocortin receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and melanocortin receptor selectivity is still unknown. We conducted comprehensive conforma-tional studies in solution of two selective antagonists of the third isoform of the melanocortin re-ceptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His6-D-Nal(2')7-NMe-Arg8-Trp9-Lys]-NH2 (15) and Ac-Nle-c[Asp-His6-D-Nal(2')7-NMe-Arg8-NMe-Trp9-NMe-Lys]-NH2 (17)...
July 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28715108/ivermectin-activates-girk-channels-in-a-pip2-dependent-g%C3%AE-%C3%AE-independent-manner-and-an-amino-acid-residue-at-the-slide-helix-governs-the-activation
#14
I-Shan Chen, Michihiro Tateyama, Yuko Fukata, Motonari Uesugi, Yoshihiro Kubo
Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl(-) channel in parasites. It is also known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. In this study, we found that the G-protein-gated inwardly rectifying K(+) (GIRK) channel is activated by IVM directly. By electrophysiological recordings in Xenopus oocytes, we observed that IVM activates GIRK channel in a phosphatidylinositol-4,5-biphosphate (PIP2 )-dependent manner, and that the IVM-mediated GIRK activation is independent of Gβγ ...
July 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28714799/in-silico-approaches-to-identify-novel-myeloid-cell-leukemia-1-mcl-1-inhibitors-for-treatment-of-cancer
#15
Ji-Xia Ren, Cheng-Ping Li, Xiu-Ling Zhou, Xue-Song Cao, Yong Xie
Myeloid cell leukemia-1 (Mcl-1) has been a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to the resistance to current chemotherapeutics. Here, we identified new Mcl-1 inhibitors using a multi-step virtual screening approach. First, based on two different ligand-receptor complexes, 20 pharmacophore models were established by simultaneously using "Receptor-Ligand Pharmacophore Generation" method and manual build feature method, and then carefully validated by a test database...
July 17, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28714400/cholinesterase-inhibitory-activity-of-some-semi-rigid-spiro-heterocycles-pom-analyses-and-crystalline-structure-of-pharmacophore-site
#16
Taibi Ben Hadda, Oualid Talhi, Artur S M Silva, Fatma Sezer Senol, Ilkay Erdogan Orhan, Abdur Rauf, Yahia N Mabkhot, Khaldoun Bachari, Ismail Warad, Thoraya A Farghaly, Ismail I Althagafi, Mohammad S Mubarak
Cholinesterase family consists of two sister enzymes; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which hydrolyze acetylcholine. Since deficit of acetylcholine has been evidenced in the patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drug class for the treatment of AD. In the present study, five compounds (2-6) with spiro skeleton have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 25 mg/mL...
July 13, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28714383/novel-mannich-bases-as-potential-anticonvulsants-syntheses-characterization-and-biological-evaluation
#17
Amit Kumar Keshari, Aseem Tewari, Shweta Singh Verma, Shailendra K Saraf
BACKGROUND: Mannich bases are known to be an important pharmacophore or bioactive leads in the synthesis of various potential agents that have a variety of therapeutic activities like anticancer, antipsychotic, anticonvulsant, antimalarial, anti-inflammatory, antibacterial and so forth. Thus, in the present research, conjugation of moieties like 1,5-benzoxazepines and 1,5-benzothiazepines with secondary amines like piperazine, methyl piperazine and morpholine was carried out in a Mannich base with an anticipation of good anticonvulsant activity...
July 17, 2017: Central Nervous System Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28714148/pd-ii-catalyzed-site-selective-c-sp3-h-alkynylation-of-oligopeptides-a-linchpin-approach-for-oligopeptide-drug-conjugation
#18
Tao Liu, Jennifer X Qiao, Michael A Poss, Jin-Quan Yu
The palladium(II)-catalyzed C(sp3)-H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif serves as a linchpin to introduce a broad range of carbonyl-containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide-pharmacophore conjugates via C-H functionalization. Dipeptide conjugates with coprostanol and estradiol has been synthesized using this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors...
July 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28710924/identification-of-new-bace1-inhibitors-using-pharmacophore-and-molecular-dynamics-simulations-approach
#19
Anantha Krishnan Dhanabalan, Manish Kesherwani, Devadasan Velmurugan, Krishnasamy Gunasekaran
Inhibition of β-Secretase (BACE1) is crucial for the treatment of Alzheimer's disease (AD). Availability of BACE1 crystal structures in both apo and complexed forms enables to find structure-based BACE1 inhibitors for controlling AD. There are two catalytic aspartates (ASP32 and ASP228) presents in the active domain of BACE1. In order to understand the binding mechanism and structure-activity relationship of amidine-containing BACE1 inhibitors, molecular docking, and pharmacophore and 3D-QSAR studies have been carried out with 34 amidine derivatives to develop a pharmacophore model...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28707592/rational-drug-design-of-antineoplastic-agents-using-3d-qsar-cheminformatic-and-virtual-screening-approaches
#20
Jelica Vucicevic, Katarina Nikolic, John B O Mitchell
BACKGROUND: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. RESULTS: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery...
July 12, 2017: Current Medicinal Chemistry
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