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https://www.readbyqxmd.com/read/28340400/pharmacoinformatics-exploration-of-polyphenol-oxidases-leading-to-novel-inhibitors-by-virtual-screening-and-molecular-dynamic-simulation-study
#1
Mubashir Hassan, Qamar Abbas, Zaman Ashraf, Ahmed A Moustafa, Sung-Yum Seo
Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis...
March 15, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28337326/crystal-structures-of-erap2-complexed-with-inhibitors-reveal-pharmacophore-requirements-for-optimizing-inhibitor-potency
#2
Anastasia Mpakali, Petros Giastas, Rebecca Deprez-Poulain, Athanasios Papakyriakou, Despoina Koumantou, Ronan Gealageas, Sofia Tsoukalidou, Dionisios Vourloumis, Irene M Mavridis, Efstratios Stratikos, Emmanuel Saridakis
Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adaptive immune responses. To better understand the structural elements of inhibitors that govern their binding affinity to the ERAP2 active site, we cocrystallized ERAP2 with a medium activity 3,4-diaminobenzoic acid inhibitor and a poorly active hydroxamic acid derivative...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28320613/synthesis-of-conformationally-restricted-1-3-dioxanes-to-analyze-the-bioactive-conformation-of-1-3-dioxane-based-%C3%AF-1-and-pcp-receptor-antagonists
#3
Samuel Asare-Nkansah, Dirk Schepmann, Bernhard Wünsch
The receptor binding profile of 2-phenyl-4-(aminoethyl)-1,3-dioxanes is dependent on the additional substituent in 2-position, the substituents at the amino moiety and the stereochemistry. Herein, conformationally restricted 1,3-dioxanes bearing an axially oriented phenyl moiety in 2-position were prepared and pharmacologically evaluated. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic system. The resulting alcohol 17 was transformed into amines 20-23 with axially (a-series) or equatorially oriented aminoethyl moiety (b-series)...
March 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28319811/protein-epitope-mimetic-macrocycles-as-biopharmaceuticals
#4
REVIEW
Anatol Luther, Kerstin Moehle, Eric Chevalier, Glenn Dale, Daniel Obrecht
Fully synthetic medium-sized macrocyclic peptides mimicking the key β-hairpin and α-helical protein epitopes relevant in many protein-protein interactions have emerged as a novel class of drugs with the potential to fill an important gap between small molecules and proteins. Conformationally stabilized macrocyclic scaffolds represent ideal templates for medicinal chemists to incorporate bioactive peptide and protein pharmacophores in order to generate novel drugs to treat diseases with high unmet medical need...
March 5, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28319782/synthesis-and-antiplasmodial-activity-of-novel-indoleamide-derivatives-bearing-sulfonamide-and-triazole-pharmacophores
#5
N Devender, Sarika Gunjan, Renu Tripathi, Rama Pati Tripathi
Due to the recent reports of growing parasite resistance to artemisinins and other antimalarial drugs, development of new antimalarial chemotypes is an urgent priority. Here in, we report a novel series of adamantyl/cycloheptyl indoleamide derivatives bearing sulfonamide and triazole pharmacophores adopting different chemical modifications and evaluated them for antiplasmodial activity in vitro. Among all the indoleamides, compounds 22, 24, 26 and 30 with sulfonamide pharmacophore showed promising activity with IC50 of 1...
March 8, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28319389/potential-antiosteoporotic-natural-product-lead-compounds-that-inhibit-17%C3%AE-hydroxysteroid-dehydrogenase-type-2
#6
Anna Vuorinen, Roger T Engeli, Susanne Leugger, Fabio Bachmann, Muhammad Akram, Atanas G Atanasov, Birgit Waltenberger, Veronika Temml, Hermann Stuppner, Liselotte Krenn, Sylvin B Ateba, Dieudonné Njamen, Rohan A Davis, Alex Odermatt, Daniela Schuster
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ(4)-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature...
March 20, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28318941/expanding-the-tetrahydroquinoline-pharmacophore
#7
Navya Goli, Prathama S Mainkar, Sudha Sravanti Kotapalli, Tejaswini K, Ramesh Ummanni, Srivari Chandrasekhar
Tetrahydroquinoline is a privileged scaffold with a large number of biological applications. The tetrahydroquinoline pharmacophore has been expanded to yield 34 compounds. Biological screening of these compounds led to the identification of tetrahydroquinoline as neurotropic agents not reported earlier.
March 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28318895/competitive-protein-tyrosine-phosphatase-1b-ptp1b-inhibitors-prenylated-caged-xanthones-from-garcinia-hanburyi-and-their-inhibitory-mechanism
#8
Xue Fei Tan, Zia Uddin, Chanin Park, Yeong Hun Song, Minky Son, Keun Woo Lee, Ki Hun Park
Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70...
March 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28318252/molecular-dynamics-in-mixed-solvents-reveals-protein-ligand-interactions-improves-docking-and-allows-accurate-binding-free-energy-predictions
#9
Juan Pablo Arcon, Lucas A Alfredo Defelipe, Carlos Pablo Modenutti, Elias Daniel Lopez, Daniel Alvarez-Garcia, Xavier Barril, Adrian Gustavo Turjanski, Marcelo A Marti
One of the most important biological processes at the molecular level is the formation of protein-ligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Due to its low cost relative to its experimental sibling, Molecular Dynamics (MD) simulations in the presence of different solvent probes mimicking specific type of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28317807/tetrahydro-2-furanyl-2-4-1h-3h-pyrimidinedione-derivatives-as-novel-antibacterial-compounds-against-mycobacterium
#10
Yuji Koseki, Hironori Kanetaka, Joji Tsunosaki, Héléne Munier-Lehmann, Shunsuke Aoki
OBJECTIVE/BACKGROUND: Mycobacterium tuberculosis thymidine monophosphate kinase (mtTMPK) is a potential enzymatic target for the treatment of tuberculosis (TB). MATERIALS AND METHODS: In this study, we performed pharmacophore-based in silico screening, targeting mtTMPK with a compound library of 461,383 chemicals. We evaluated the candidate compounds for inhibitory effects on the growth of the model mycobacteria, Mycobacterium smegmatis. RESULTS: The compound KTP3 completely inhibited the growth of M...
January 2017: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/28317396/3d-qsar-studies-pharmacophore-modeling-and-virtual-screening-of-diarylpyrazole-benzenesulfonamide-derivatives-as-a-template-to-obtain-new-inhibitors-using-human-carbonic-anhydrase-ii-as-a-model-protein
#11
Yeganeh Entezari Heravi, Hassan Sereshti, Ali Akbar Saboury, Jahan Ghasemi, Marzieh Amirmostofian, Claudiu T Supuran
A 3D-QSAR modeling was performed on a series of diarylpyrazole-benzenesulfonamide derivatives acting as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The compounds were collected from two datasets with the same scaffold, and utilized as a template for a new pharmacophore model to screen the ZINC database of commercially available derivatives. The datasets were divided into training, test, and validation sets. As the first step, comparative molecular field analysis (CoMFA), CoMFA region focusing and comparative molecular similarity indices analysis (CoMSIA) in parallel with docking studies were applied to a set of 41 human (h) CA II inhibitors...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28317151/design-synthesis-and-evaluation-of-the-kinase-inhibition-potential-of-pyridylpyrimidinylaminophenyl-derivatives
#12
Priyanka Manchanda, Badri Parshad, Amit Kumar, Rakesh K Tiwari, Amir N Shirazi, Keykavous Parang, Sunil K Sharma
In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8...
March 20, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28316236/webmolcs-a-web-based-interface-for-visualizing-molecules-in-3d-chemical-spaces
#13
Mahendra Awale, Daniel Probst, Jean-Louis Reymond
The concept of chemical space provides a convenient framework to analyze large collections of molecules by placing them in property spaces where distances represent similarities. Here we report webMolCS, a new type of web-based interface visualizing up to 5000 user-defined molecules in six different 3D chemical spaces obtained by principal component analysis or similarity mapping of multi-dimensional property spaces describing composition (MQN: 42D Molecular Quantum Numbers, SMIfp: 34D SMILES fingerprint), shapes and pharmacophores (APfp: 20D atom pair fingerprint, Xfp: 55D category extended atom pair fingerprint), and substructures (Sfp: 1024D binary substructure fingerprint, ECfp4: 1024D extended connectivity fingerprint)...
March 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28315689/in-silico-prediction-of-hpxr-activators-using-structure-based-pharmacophore-modeling
#14
Nao Torimoto-Katori, Ruili Huang, Harutoshi Kato, Rikiya Ohashi, Menghang Xia
The activation of pregnane X receptor (PXR), a member of the nuclear receptor superfamily, can mediate potential drug-drug interactions by regulating the expression of several drug- mediated enzymes and transporters, resulting in reduced therapeutic efficacy or increased toxicity by producing reactive metabolites. Therefore, in the early stage of drug development, it is important to predict these risks using an in silico approach. We constructed a human PXR (hPXR) pharmacophore model based on known structural information of compounds that activate PXR...
March 15, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28304162/rational-design-synthesis-and-biological-evaluation-of-heterocyclic-quinolones-targeting-the-respiratory-chain-of-mycobacterium-tuberculosis
#15
Weiqian David Hong, Peter D Gibbons, Suet C Leung, Richard Amewu, Paul A Stocks, Andrew Valentine Stachulski, Pedro C Horta, Maria Lurdes Santos Cristiano, Alison E Shone, Darren Moss, Alison Ardrey, Raman Sharma, Ashley J Warman, Paul T P Bedingfield, Nicholas E Fisher, Ghaith Aljayyoussi, Sally Mead, Maxine Caws, Neil G Berry, Stephen A Ward, Giancarlo A Biagini, Paul M O'Neill, Gemma Louise Nixon
A High-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). 11,000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11,000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ~100 hits and four distinct chemotypes, the most promising of which contained the quinolone core...
March 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28302490/a-novel-quinazoline-based-analog-induces-g2-m-cell-cycle-arrest-and-apoptosis-in-human-a549-lung-cancer-cells-via-a-ros-dependent-mechanism
#16
Hailong Shi, Yan Li, Xiaorong Ren, Yaohong Zhang, Zhen Yang, Chenze Qi
6-amino-4-(4-phenoxyphenylethylamino)quinazoline (QNZ) is an excellent quinazoline-containing NF-κB inhibitor also acting as a novel anticancer agent. Considering both the medicinal significance of quinazoline scaffold and the tunable functionality of Michael acceptor-centric pharmacophores in the electrophilicity-based prooxidant strategy, we designed a novel QNZ-inspired electrophilic molecule QNZ-A by introducing a Michael acceptor unit at position-6 of quinazoline ring in QNZ. Our results identified QNZ-A as a promising selective cytotoxic agent against A549 cells...
March 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28302400/substrate-and-inhibitor-specificity-of-kynurenine-monooxygenase-from-cytophaga-hutchinsonii
#17
Robert S Phillips, Andrew D Anderson, Harvey G Gentry, Osman F Güner, J Phillip Bowen
Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine...
March 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28302310/design-synthesis-and-anti-diabetic-activity-of-triazolotriazine-derivatives-as-dipeptidyl-peptidase-4-dpp-4-inhibitors
#18
Bhumika D Patel, Shraddha V Bhadada, Manjunath D Ghate
Type 2 diabetes mellitus (T2DM) is one of the major global metabolic disorders characterized by insulin resistance and chronic hyperglycemia. Inhibition of the enzyme, dipeptidyl peptidase-4 (DPP-4) has been proved as successful and safe therapy for the treatment of T2DM since last decade. In order to design novel DPP-4 inhibitors, various in silico studies such as 3D-QSAR, pharmacophore modeling and virtual screening were performed and on the basis of the combined results of them, total 50 triazolo[5,1-c][1,2,4]triazine derivatives were designed and mapped on the best pharmacophore model...
March 6, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28302029/in-silico-adme-studies-for-new-drug-discovery-from-chemical-compounds-to-chinese-herbal-medicines
#19
Guojun Yan, Xiaobing Wang, Zhou Chen, Xianhui Wu, Jinhuo Pan, Yushen Huang, Gang Wan, Zhaogang Yang
Nowadays, in-silico tools are widely used to provide the potential structure of the metabolites formed depending on the site of metabolism. These methods can also highlight the molecular moieties that help to direct the molecule into the cytochrome cavity so that the site of metabolism is in proximity to the catalytic center. In this mini-review, we summarized three aspects of the in-silico methods in the application of prediction the ADME (absorption, distribution, metabolism and excretion) properties of compounds: structure-based approaches for predicting molecular modeling of drug metabolizing enzymes; in-silico metabolite prediction; and pharmacophore models for analysis substrate specificity...
March 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28302027/in-silico-design-and-admet-studies-of-natural-compounds-as-inhibitors-of-xanthine-oxidase-xo-enzyme
#20
Neelam Malik, Priyanka Dhiman, Anurag Khatkar
BACKGROUND: Xanthine oxidase a ubiquitous enzyme has been found to be involved in various pathological disorders including gout, hyperuricemia, inflammation, oxidative stress and cardiovascular diseases. Inhibitors of xanthine oxidase thus find a crucial role in the therapeutic treatment of these deadly diseases. OBJECTIVE: Considering the side effects of today's treatment regimen here we choose nature based compounds to act as xanthine oxidase inhibitors. In the present work, we performed in-silico docking of natural compounds to reveal the underlying mechanism of inhibition of xanthine oxidase...
March 15, 2017: Current Drug Metabolism
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