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https://www.readbyqxmd.com/read/28813605/structure-activity-relationship-studies-on-a-macrocyclic-agouti-related-protein-agrp-scaffold-reveal-agouti-signaling-protein-asp-residue-substitutions-maintain-melanocortin-4-receptor-antagonist-potency-and-result-in-inverse-agonist-pharmacology-at-the-melanocortin
#1
Mark D Ericson, Katie T Freeman, Sathya M Schnell, Katlyn A Fleming, Carrie Haskell-Luevano
The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists...
August 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28813419/vaccine-driven-pharmacodynamic-dissection-and-mitigation-of-fenethylline-psychoactivity
#2
Cody J Wenthur, Bin Zhou, Kim D Janda
Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28811071/biological-evaluation-of-2-pyrazolinyl-1-carbothioamide-derivatives-against-hct116-human-colorectal-cancer-cell-lines-and-elucidation-on-qsar-and-molecular-binding-modes
#3
Beom Soo Kim, Soon Young Shin, Seunghyun Ahn, Dongsoo Koh, Young Han Lee, Yoongho Lim
In the search of compounds exhibiting anticancer activity, 37 derivatives of 2-pyrazolinyl-1-carbothioamide were designed and synthesized. Clonogenic cell survival assays were adapted to measure the cytotoxicities of the synthetic derivatives against HCT116 human colon cancer cell lines. Half-maximal cell growth inhibitory concentrations (GI50) ranged from 0.49 to 41.22µM. The compound with the lowest GI50 value, 3-(2-hydroxy-4,5-dimethoxyphenyl)-5-(naphthalen-1-yl)-N-(3,4,5-trimethoxyphenyl)-pyrazolinyl-1-carbothioamide, was subjected to further biological studies, including cell viability and apoptosis assays to examine levels of annexin-V in the outer plasma membrane layer and poly ADP-ribose polymerase cleavage...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28809552/characterization-of-2-oxindole-forming-heme-enzyme-mare-expanding-the-functional-diversity-of-the-tryptophan-dioxygenase-superfamily
#4
Yuyang Zhang, Yi Zou, Nelson L Brock, Tingting Huang, Yingxia Lan, Xiaozheng Wang, Zixin Deng, Yi Tang, Shuangjun Lin
3-Substituted 2-oxindoles are important structural motifs found in many biologically active natural products and pharmaceutical lead compounds. Here, we report an enzymatic formation of the 3-substituted 2-oxindoles catalyzed by MarE in the maremycin biosynthetic pathway in Streptomyces sp. B9173. MarE is a homologue of Fe(II)/heme-dependent tryptophan 2,3-dioxygenases (TDOs). Typical TDOs usually catalyze the insertion of two oxygen atoms from O2 into an indole ring to generate N-formylkynurenine (NFK)-like products...
August 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28809439/in-silico-profiling-of-the-biological-activities-of-amaryllidaceae-alkaloids
#5
Eman Shawky
OBJECTIVES: The large number of publications about Amaryllidaceae alkaloids reflects the abundance and variety in biological activity of these alkaloids. An in-silico approach was implemented in this work to rationalize the individual alkaloids to molecular biological activity. METHODS: A database was generated containing 313 Amaryllidaceae alkaloids which were then subjected to in-silico-validated structure-based virtual screening using extra precision (XP) approach of Glide docking program...
August 15, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28808272/a-combinatorial-approach-for-the-discovery-of-cytochrome-p450-2d6-inhibitors-from-nature
#6
Johannes Hochleitner, Muhammad Akram, Martina Ueberall, Rohan A Davis, Birgit Waltenberger, Hermann Stuppner, Sonja Sturm, Florian Ueberall, Johanna M Gostner, Daniela Schuster
The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28806082/the-discovery-of-novel-antimalarial-aminoxadiazoles-as-a-promising-nonendoperoxide-scaffold
#7
Elena Sandoval, María José Lafuente-Monasterio, María J Almela, Pablo Castañeda, María Belén Jiménez Díaz, María S Martínez-Martínez, Jaume Vidal, Íñigo Angulo-Barturen, Paul Bamborough, Jeremy Burrows, Nicholas Cammack, María J Chaparro, José M Coterón, Cristina de Cozar, Benigno Crespo, Beatriz Díaz, Gerard Drewes, Esther Fernández, Santiago Ferrer-Bazaga, María Teresa Fraile, Francisco J Gamo, Sonja Ghidelli-Disse, Rubén Gómez, John Haselden, Sophie Huss, María Luisa León, Jaime de Mercado, Simon J F Macdonald, José Ignacio Martín Hernando, Sara Prats, Margarita Puente, Anne Rodríguez, Juan C de la Rosa, Lourdes Rueda, Carolyn Selenski, Paul Willis, David M Wilson, Michael Witty, Félix Calderón
Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy...
August 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28804613/novel-derivatives-of-phthalimide-with-potent-anticonvulsant-activity-in-ptz-and-mes-seizure-models
#8
Asghar Davood, Maryam Iman, Hanieh Pouriaiee, Hamed Shafaroodi, Sepideh Akhbari, Leila Azimidoost, Erfan Imani, Somaieh Rahmatpour
OBJECTIVES: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. MATERIALS AND METHODS: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models...
April 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28802212/pharmacophore-based-design-of-some-multi-targeted-compounds-targeted-against-pathways-of-diabetic-complications
#9
Navriti Chadha, Om Silakari
Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc...
July 21, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28802152/comparison-and-analysis-of-the-structures-and-binding-modes-of-antifungal-se-and-cyp51-inhibitors
#10
Bin Sun, Wanxu Huang, Min Liu, Kang Lei
With the abuse of clinical broad-spectrum antimicrobial agents, immunosuppressive agents, chemotherapy drugs, the emergence of pathogenic fungi resistance is more and more frequent. However, there is still no effective treatment for the fungal resistance. Squalenee epoxidase (SE) and 14 α-demethylase (CYP51) are important antifungal drug targets. In order to achieve a deeper insight into the structural characteristics and the action modes of SE and CYP51inhibitors, the homology model of SE (Candida albicans) was constructed using monooxygenase of Pseudomonas aeruginosa as template, and the reliability of model was confirmed by Ramachandran plots and Verify 3D...
August 1, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28799177/racemic-and-enantiopure-forms-of-3-ethyl-3-phenylpyrrolidin-2-one-adopt-very-different-crystal-structures
#11
Arcadius V Krivoshein, Sergey V Lindeman, Tatiana V Timofeeva, Victor N Khrustalev
3-Ethyl-3-phenylpyrrolidin-2-one (EPP) is an experimental anticonvulsant based on the newly proposed α-substituted amide group pharmacophore. These compounds show robust activity in animal models of drug-resistant epilepsy and are thus promising for clinical development. In order to understand pharmaceutically relevant properties of such compounds, we are conducting an extensive investigation of their structures in the solid state. In this article, we report chiral high-performance liquid chromatography (HPLC) separation, determination of absolute configuration of enantiomers, and crystal structures of EPP...
August 11, 2017: Chirality
https://www.readbyqxmd.com/read/28797884/drifting-of-heme-coordinating-group-in-imidazolylmethylxanthones-leading-to-improved-selective-inhibition-of-cyp11b1
#12
Silvia Gobbi, Qingzhong Hu, Christina Zimmer, Federica Belluti, Angela Rampa, Rolf W Hartmann, Alessandra Bisi
An abnormal increase in glucocorticoid levels is responsible for pathological disorders affecting different organs and systems, and the selective inhibition of appropriate steroidogenic enzymes represents a validated strategy to restore their physiological levels. In continuing our studies on CYP11B inhibitors, in this paper a small series of 6-substituted 3-imidazolylmethylxanthones was designed and synthesized, according to the data acquired from previously reported series of derivatives and from a purposely-performed docking study...
August 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28797773/methyl-propiolate-and-3-butynone-starting-points-for-synthesis-of-amphiphilic-1-2-3-triazole-peptidomimetics-for-antimicrobial-evaluation
#13
Thomas A Bakka, Morten B Strøm, Jeanette H Andersen, Odd R Gautun
A library of 29 small 1,4-substituted 1,2,3-triazoles was prepared for studies of antimicrobial activity. The pharmacophore model investigated with these substrates was based on small peptidomimetics of antimicrobial peptides and antimicrobials isolated from marine organisms from sub-arctic regions. Using methyl 1,2,3-triazole-carboxylates and 1,2,3-triazole methyl ketones prepared through "click" chemistry we were able to synthesize the different cationic amphiphiles through three steps or less. Several structural modifications to the lipopohilic side and hydrophilic sides of the amphiphiles were investigated and compared with regards to antimicrobial activity and cytotoxicity in particular...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28795372/development-of-a-pharmacophore-for-cruzain-using-oxadiazoles-as-virtual-molecular-probes-quantitative-structure-activity-relationship-studies
#14
Anacleto S de Souza, Marcelo T de Oliveira, Adriano D Andricopulo
Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR ([Formula: see text] = 0.81) and a 3D-QSAR-based pharmacophore ([Formula: see text] = 0...
August 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28793831/deciphering-the-crucial-molecular-properties-of-a-series-of-benzothiazole-hydrazone-inhibitors-that-targets-anti-apoptotic-bcl-xl-protein
#15
Parthiban Marimuthu, Pavithra K Balasubramanian, Kalaimathy Singaravelu
The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently,molecular series of BenzothiazoleHydrazone(BH) inhibitorsthat exhibits drug-likenesscharacteristics,whichselectivelytargets Bcl-xLhave been reported.In the present study,dockingwas used toexplore the plausible binding mode of the highly active BH inhibitorwith Bcl-xL;and Molecular Dynamics(MD) simulation wasapplied toinvestigate the stability of predicted conformationover time...
August 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28790989/a-proposal-for-a-structural-model-of-the-feline-calicivirus-protease-bound-to-the-substrate-peptide-under-physiological-conditions
#16
Masaru Yokoyama, Tomoichiro Oka, Hirotaka Takagi, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Yukinobu Tohya, Hironori Sato
Feline calicivirus (FCV) protease functions to cleave viral precursor proteins during productive infection. Previous studies have mapped a protease-coding region and six cleavage sites in viral precursor proteins. However, how the FCV protease interacts with its substrates remains unknown. To gain insights into the interactions, we constructed a molecular model of the FCV protease bound with the octapeptide containing a cleavage site of the capsid precursor protein by homology modeling and docking simulation...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28789944/prioritization-of-natural-compounds-against-mycobacterium-tuberculosis-3-dehydroquinate-dehydratase-a-combined-in-silico-and-in-vitro-study
#17
Mohsin Y Lone, Mohd Athar, Vivek K Gupta, Prakash C Jha
Enormous efforts have been endeavored to develop inhibitors against the potential therapeutic target, mycobacterium tuberculosis 3-dehydroquinate dehydratase (MtbDHQase) to combat resistance. Over a dozen of small molecules have been crystallized to characterize the structural basis of the inhibition. However, the studies accomplished so far, have not incorporated all the essential interactions of these complexes simultaneously, to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore models and identify the essential features that can be employed to prioritize the molecules against this target...
August 5, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28782938/first-in-class-inhibitor-of-ribosomal-rna-synthesis-with-antimicrobial-activity-against-staphylococcus-aureus
#18
Xiao Yang, Ming Jing Luo, Apple C M Yeung, Peter J Lewis, Paul K S Chan, Margaret Ip, Cong Ma
We report discovery of the first bacterial ribosomal RNA (rRNA) synthesis inhibitor that has specific antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). A pharmacophore model was constructed based on the protein-protein interaction between essential bacterial rRNA transcription factors NusB and NusE, and employed for an in silico screen to identify potential leads. One compound, (E)-2-[[(3-ethynylphenyl)imino]methyl]-4-nitrophenol (MC4), demonstrated antimicrobial activity against a panel of S...
August 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28781163/polypharmacology-of-conformationally-locked-methanocarba-nucleosides
#19
REVIEW
Kenneth A Jacobson, Dilip K Tosh, Kiran S Toti, Antonella Ciancetta
A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities...
August 3, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28776992/hydrophilic-potent-and-selective-7-substituted-2-aminoquinolines-as-improved-human-neuronal-nitric-oxide-synthase-inhibitors
#20
Anthony V Pensa, Maris A Cinelli, Huiying Li, Georges Chreifi, Paramita Mukherjee, Linda J Roman, Pavel Martásek, Thomas L Poulos, Richard B Silverman
Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342...
August 4, 2017: Journal of Medicinal Chemistry
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