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https://www.readbyqxmd.com/read/28442756/crystal-structure-based-discovery-of-a-novel-synthesized-parp1-inhibitor-ol-1-with-apoptosis-inducing-mechanisms-in-triple-negative-breast-cancer
#1
Leilei Fu, Shuya Wang, Xuan Wang, Peiqi Wang, Yaxin Zheng, Dahong Yao, Mingrui Guo, Lan Zhang, Liang Ouyang
Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28442252/approaches-towards-the-development-of-chimeric-dpp4-ace-inhibitors-for-treating-metabolic-syndrome
#2
Jitendra A Sattigeri, Sachin Sethi, Joseph A Davis, Shahadat Ahmed, Geeta V Rayasam, Balasaheb G Jadhav, Satya M Chilla, Dhrubajyoti Datta, A Gadhave, Vamshi K Tulasi, Tarun Jain, Sreedhara Voleti, Biju Benjamin, Sunitha Udupa, Garima Jain, Yogender Singh, Kona Srinivas, Vinay S Bansal, Abhijit Ray, Pradip K Bhatnagar, Ian A Cliffe
Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28441581/design-combinatorial-synthesis-and-biological-evaluations-of-novel-3-amino-1-1-aryl-1h-1-2-3-triazol-5-yl-methyl-2-oxospiro-benzo-a-pyrano-2-3-c-phenazine-1-3-indoline-2-carbonitrile-antitumor-hybrid-molecules
#3
Yuanyuan Lu, Linlin Wang, Xiaobing Wang, Tao Xi, Jianmin Liao, Zhixiang Wang, Feng Jiang
A combinatorial chemical library of fifty-nine novel 3-amino-1'-((1-aryl-1H-1,2,3-triazol-5-yl)methyl)-2'-oxospiro[benzo[a]pyrano[2,3-c]phenazine-1,3'-indoline]-2-carbonitrile, designed as hybrid molecules of phenazine, pyran, indole and 1,2,3-triazole pharmacophores, were constructed in this study. Cytotoxic evaluation indicated that some compounds exhibited moderate cytotoxicity against HCT116, MCF7, HepG2 and A549 cancer cell lines in vitro, in which compound 36 was found to have best antiproliferative activity against the A549 cancer cell line with IC50 value of 5...
April 18, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28441580/the-computer-aided-discovery-of-novel-family-of-the-5-ht6-serotonin-receptor-ligands-among-derivatives-of-4-benzyl-1-3-5-triazine
#4
Dorota Łażewska, Rafał Kurczab, Małgorzata Więcek, Katarzyna Kamińska, Grzegorz Satała, Magdalena Jastrzębska-Więsek, Anna Partyka, Andrzej J Bojarski, Anna Wesołowska, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik
The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4 receptor but fitted in 3/4 of pharmacophore features of the 5-HT6R ligand, occurred to be a moderate 5-HT6R agent, useful as a lead structure for further modifications. A series of new derivatives (3-19) of the lead 2 was synthesized, evaluated in the radioligand binding assay (RBA) and explored in comprehensive molecular modelling, including both pharmacophore- and structure-based approaches with docking to the homology model of 5-HT6R...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28438631/in-vivo-inhibitory-activity-of-andrographolide-derivative-adn-9-against-liver-cancer-and-its-mechanisms-involved-in-inhibition-of-tumor-angiogenesis
#5
Wei Yang, Jin Zhao, Yake Wang, Haiwei Xu, Zhenwei Wu, Yangyang Hu, Kunkun Jiang, Pengpeng Shen, Cuiyun Ma, Zhenzhen Guan, Yan Zhang, Jiahui Ma, Ning Shang, Guangming Yan, Zhenji Wang, Guifu Dai
It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro...
April 21, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28435536/norbenzomorphan-scaffold-chemical-tool-for-modulating-sigma-receptor-subtype-selectivity
#6
James J Sahn, Timothy R Hodges, Jessica Z Chan, Stephen F Martin
Some norbenzomorphans exhibit high affinity for sigma 1 and sigma 2 receptors, and varying the position of substituents on the aromatic ring of this scaffold has a significant effect on subtype selectivity. In particular, compounds bearing several different substituents at C7 of the norbenzomorphan ring system exhibit a general preference for the sigma 1 receptor, whereas the corresponding C8-substituted analogues preferentially bind at the sigma 2 receptor. These findings suggest that the norbenzomorphan scaffold may be a unique chemical template that can be easily tuned to prepare small molecules for use as tool compounds to study the specific biological effects arising from preferential binding at either sigma receptor subtype...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28435525/development-and-biological-evaluation-of-a-photoactivatable-small-molecule-microtubule-targeting-agent
#7
Alexander Döbber, Athena F Phoa, Ramzi H Abbassi, Brett W Stringer, Bryan W Day, Terrance G Johns, Mohammed Abadleh, Christian Peifer, Lenka Munoz
Photoremovable protecting groups added to bioactive molecules provide spatial and temporal control of the biological effects. We present synthesis and characterization of the first photoactivatable small-molecule tubulin inhibitor. By blocking the pharmacophoric OH group on compound 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photocaged prodrug 2 that had no effect in biological assays. Short UV light exposure of the derivative 2 or UV-irradiation of cells treated with 2 resulted in fast and potent inhibition of tubulin polymerization, attenuation of cell viability, and apoptotic cell death, implicating release of the parent active compound...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28435427/novel-4-thiazolidinone-derivatives-as-agonists-of-benzodiazepine-receptors-design-synthesis-and-pharmacological-evaluation
#8
Mehrdad Faizi, Reza Jahani, Seyed Abbas Ebadi, Sayyed Abbas Tabatabai, Elham Rezaee, Mehrnaz Lotfaliei, Mohsen Amini, Ali Almasirad
A new series of 4-chloro-N-(2-(substitutedphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide derivatives were designed, synthesized and biologically evaluated as anticonvulsant agents. The designed compounds have the main essential functional groups for binding to the benzodiazepine receptors and 4-thiazolidinone ring as an anticonvulsant pharmacophore. Some of the new synthesized compounds showed considerable anticonvulsant activity in electroshock and pentylenetetrazole-induced lethal convulsion tests. Compound 5i, 4-chloro-N-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-phenoxybenzamide, with the best activity was selected for evaluation of other benzodiazepine pharmacological effects...
2017: EXCLI journal
https://www.readbyqxmd.com/read/28431879/improvement-of-herg-romk-index-of-spirocyclic-romk-inhibitors-through-scaffold-optimization-and-incorporation-of-novel-pharmacophores
#9
Shuzhi Dong, Kelsey VanGelder, Zhi-Cai Shi, Yang Yu, Zhicai Wu, Ron Ferguson, Zack Zhiqiang Guo, Haifeng Tang, Jessica Frie, Qinghong Fu, Xin Gu, Birgit T Priest, Brande Thomas-Fowlkes, Adam Weinglass, Michael Margulis, Jessica Liu, Lee-Yuh Pai, Caryn Hampton, Robin E Haimbach, Karen Owens, Vincent Tong, Shiyao Xu, Mengwei Hu, Gloria J Zingaro, Pierre Morissette, Juliann Ehrhart, Sophie Roy, Kathleen Sullivan, Alexander Pasternak
SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone...
March 30, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28429411/nanodiscs-for-inpharma-nmr-characterization-of-gpcrs-ligand-binding-to-the-human-a2a-adenosine-receptor
#10
Kai Fredriksson, Philip Lottmann, Sonja Hinz, Iounut Onila, Aliaksei Shymanets, Christian Harteneck, Christa E Müller, Christian Griesinger, Thomas E Exner
G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2A R with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A2A R...
April 21, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28422491/discovery-of-novel-ligands-for-tnf-%C3%AE-and-tnf-receptor-1-through-structure-based-virtual-screening-and-biological-assay
#11
Si Chen, Zhiwei Feng, Yun Wang, Shifan Ma, Ziheng Hu, Peng Yang, Yifeng Chai, Xiang-Qun Sean Xie
Tumor Necrosis Factor alpha (TNF-α) is overexpressed in various diseases, and it has been a validated therapeutic target for autoimmune diseases. All therapeutics currently used targeting TNF-α are biomacromolecules, and limited numbers of TNF-α chemical inhibitors have been reported, which makes the identification of small molecule alternatives in urgent need. Recent studies mainly focused on identifying small molecules that directly bind to TNF-α or TNF receptor-1 (TNFR1), and/or inhibit the interaction between TNF-α and TNFR1, and/or regulate related signaling pathways...
April 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28419930/design-synthesis-and-anticancer-potential-of-nsc-319745-hydroxamic-acid-derivatives-as-dnmt-and-hdac-inhibitors
#12
Zigao Yuan, Qinsheng Sun, Dan Li, Shuangshuang Miao, Shaopeng Chen, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang
DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are important epigenetic targets during anticancer drug development. Recent study indicates that DNMT inhibitors and HDAC inhibitors display synergistic effects in certain cancers, therefore, development of molecules targeting both DNMT and HDAC is of therapeutic advantage against these cancers. Based on the structure of DNMT inhibitor NSC-319745 and the pharmacophore characteristics of HDAC inhibitors, a series of hydroxamic acid derivatives of NSC-319745 were designed and synthesized as DNMT and HDAC multifunctional inhibitors...
April 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28419928/design-synthesis-and-biological-evaluation-of-3-substituted-2-oxindole-hybrid-derivatives-as-novel-anticancer-agents
#13
Romeo Romagnoli, Pier Giovanni Baraldi, Filippo Prencipe, Paola Oliva, Stefania Baraldi, Maria Kimatrai Salvador, Luisa Carlota Lopez-Cara, Roberta Bortolozzi, Elena Mattiuzzo, Giuseppe Basso, Giampietro Viola
The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28419717/ligand-recognition-properties-of-the-vasopressin-v2-receptor-studied-under-qsar-and-molecular-modeling-strategies
#14
Marlet Martínez-Archundia, Brenda Colín-Astudillo, L M Moreno-Vargas, G Ramírez-Galicia, R Garduño-Juárez, O Deeb, Martha C Contreras-Romo, A Quintanar-Stephano, Edgar Abarca-Rojano, José Correa-Basurto
The design of new drugs that target vasopressin 2 receptor (V2R) is of vital importance to develop new therapeutic alternatives to treat diseases such as heart failure, polycystic kidney disease, etc. To get structural insights related to V2R-ligand recognition, we have used a combined approach of docking, molecular dynamics simulations (MD) and quantitative structure-activity relationship (QSAR) to elucidate the detailed interaction of the V2R with 119 of its antagonists. The three-dimensional model of V2R was built by threading methods refining its structure through MD simulations upon which the 119 ligands were subjected to docking studies...
April 17, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28417945/one-pot-phosphate-mediated-synthesis-of-novel-1-3-5-trisubstituted-pyridinium-salts-a-new-family-of-s-aureus-inhibitors
#15
Thomas Pesnot, Markus C Gershater, Martin Edwards, John M Ward, Helen C Hailes
Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give 1,3,5-pyridinium salts. The reaction, carried out at pH 6, provides conditions suitable for the use of less stable aldehydes and amines in this Chichibabin pyridine condensation...
April 12, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28417668/exploring-molecular-structural-requirement-for-ache-inhibition-through-multi-chemometric-and-dynamics-simulation-analyses
#16
Tabassum Hossain, Achintya Saha, Arup Mukherjee
The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid β-peptide (Aβ) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-à-vis inhibiting enzyme activity...
April 18, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28411471/qsar-docking-studies-of-1-3-thiazinan-3-yl-isonicotinamide-derivatives-for-antitubercular-activity
#17
Trupti S Chitre, Kalyani D Asgaonkar, Shital M Patil, Shiva Kumar, Vijay M Khedkar, Dinesh R Garud
The enzyme - enoyl acyl carrier protein reductase (enoyl ACP reductase) is a validated target for antitubercular activity. Inhibition of this enzyme interferes with mycolic acid synthesis which is crucial for Mycobacterium tuberculosis cell growth. In the present work 2D and 3D quantitative structure activity relationship (QSAR) studies were carried out on a series of thiazinan-Isoniazid pharmacophore to design newer analogues. For 2D QSAR, the best statistical model was generated using SA-MLR method (r(2)=0...
March 30, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28411325/a-literature-update-elucidating-production-of-panax-ginsenosides-with-a-special-focus-on-strategies-enriching-the-anti-neoplastic-minor-ginsenosides-in-ginseng-preparations
#18
REVIEW
Tanya Biswas, A K Mathur, Archana Mathur
Ginseng, an oriental gift to the world of healthcare and preventive medicine, is among the top ten medicinal herbs globally. The constitutive triterpene saponins, ginsenosides, or panaxosides are attributed to ginseng's miraculous efficacy towards anti-aging, rejuvenating, and immune-potentiating benefits. The major ginsenosides such as Rb1, Rb2, Rc, Rd., Re, and Rg1, formed after extensive glycosylations of the aglycone "dammaranediol," dominate the chemical profile of this genus in vivo and in vitro. Elicitations have successfully led to appreciable enhancements in the production of these major ginsenosides...
April 14, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28409625/privileged-structural-motif-detection-and-analysis-using-generative-topographic-maps
#19
Shilva Kayastha, Dragos Horvath, Erik Gilberg, Michael Gütschow, Jürgen Bajorath, Alexandre Varnek
Identification of "privileged structural motifs" associated with specific target families is of particular importance for designing novel bioactive compounds. Here, we demonstrate that they can be extracted from a data distribution represented on a two-dimensional map obtained by Generative Topographic Mapping (GTM) . In GTM, structurally related molecules are grouped together on the map. Zones of the map preferentially populated by target-specific compounds were delineated, which helped to capture common substructures on the basis of which these compounds were grouped together by the GTM...
April 14, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28408532/-68-ga-thp-psma-a-pet-imaging-agent-for-prostate-cancer-offering-rapid-room-temperature-one-step-kit-based-radiolabeling
#20
Jennifer D Young, Vincenzo Abbate, Cinzia Imberti, Levente K Meszaros, Michelle T Ma, Samantha Y A Terry, Robert C Hider, Greg E Mullen, Philip J Blower
The clinical impact and accessibility of (68)Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, one-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of (99m)Tc radiopharmaceuticals. Currently, chelating agents used in (68)Ga radiopharmaceuticals do not meet this ideal. AIM: To develop and evaluate preclinically a (68)Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of (68)Ga generator eluate to a cold kit...
April 13, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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