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Future Medicinal Chemistry

Robert Cooke, Miles Congreve
No abstract text is available yet for this article.
October 14, 2016: Future Medicinal Chemistry
Juliane K Mueller, Cathrin Rohleder, F Markus Leweke
No abstract text is available yet for this article.
October 14, 2016: Future Medicinal Chemistry
Giulia Caron, Giuseppe Ermondi
No abstract text is available yet for this article.
October 14, 2016: Future Medicinal Chemistry
Simona Panella, Maria Elena Marcocci, Ignacio Celestino, Sergio Valente, Clemens Zwergel, Domenica Donatella Li Puma, Lucia Nencioni, Antonello Mai, Anna Teresa Palamara, Giovanna Simonetti
AIM: Histone deacetylases (HDACs) regulate the life-cycle of several viruses. We investigated the ability of different HDAC-inhibitors, to interfere with influenza virus A/Puerto Rico/8/34/H1N1 (PR8 virus) replication in Madin-Darby canine kidney and NCI cells. RESULTS: 3-(5-(3-Fluorophenyl)-3-oxoprop-1-en-1-yl)-1-methyl-1H-pyrrol-2-yl)-N-hydroxyacrylamide (MC1568) inhibited HDAC6/8 activity and PR8 virus replication, with decreased expression of viral proteins and their mRNAs...
October 14, 2016: Future Medicinal Chemistry
Jeffrey J Coleman, Tomomi Komura, Julia Munro, Michael P Wu, Rakhee R Busanelli, Angela N Koehler, Méryl Thomas, Florence F Wagner, Edward B Holson, Eleftherios Mylonakis
AIM: Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE), the major constituent of propolis, is able to increase the survival of the nematode Caenorhabditis elegans after infection with the fungal pathogen Candida albicans. RESULTS: CAPE increases the expression of several antimicrobial proteins involved in the immune response to C. albicans. Structural derivatives of CAPE were synthesized to identify structure-activity relationships and decrease metabolic liability, ultimately leading to a compound that has similar efficacy, but increased in vivo stability...
October 14, 2016: Future Medicinal Chemistry
Yaxia Yuan, Xiaoqin Huang, Jun Zhu, Chang-Guo Zhan
This is a brief review of computational modeling studies on the detailed structures and mechanism of human dopamine transporter (hDAT), as well as its interaction with HIV-1 transactivator of transcription (Tat). Extensive molecular modeling, docking and dynamics simulations have resulted in reasonable structural models of hDAT in three typical conformational states, its dopamine uptake mechanism and its interaction with Tat. The obtained hDAT models in different conformational states and their complexes with dopamine and Tat have provided novel structural and mechanistic insights concerning how hDAT uptakes dopamine and how Tat affects the dopamine uptake by hDAT...
October 14, 2016: Future Medicinal Chemistry
Xin-Mei Peng, Li-Ping Peng, Shuo Li, Avula Srinivasa Rao, Kannekanti Vijaya Kumar, Shao-Lin Zhang, Kin Yip Tam, Cheng-He Zhou
AIM: Due to bacterial drug resistance, a new series of quinazolinone azolyl ethanols were synthesized and evaluated. RESULTS: In vitro antibacterial assay showed that triazolyl ethanol quinazolinone 3a was the most active compound, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimal inhibitory concentration value of 8 µg/ml, which was superior to chloromycin and comparable to norfloxacin. Molecular docking study displayed that compound 3a could interact with MRSA DNA by the formation of hydrogen bonds...
September 26, 2016: Future Medicinal Chemistry
Xiayang Xie, Lixia Gao, Austin Y Shull, Yong Teng
Peptide-based drug discovery has experienced a remarkable resurgence within the past decade due to the emerging class of inhibitors known as stapled peptides. Stapled peptides are therapeutic protein mimetics that have been locked within a specific conformational structure by hydrocarbon stapling. These peptides are highly important in selectively impairing disease-relevant protein-protein interactions and exhibit significant pharmacokinetic advantages over other forms of therapeutics in terms of affinity, specificity, size, synthetic accessibility and resistance to proteolytic degradation...
September 21, 2016: Future Medicinal Chemistry
Syed Nasir Abbas Bukhari, Gianluigi Lauro, Ibrahim Jantan, Chin Fei Chee, Muhammad Wahab Amjad, Giuseppe Bifulco, Hassan Sher, Iskandar Abdullah, Noorsaadah Abd Rahman
AIM: In present study, the anti-inflammatory activities of a new series of benzimidazole derivatives were studied, investigating their inhibition of secretory phospholipase A2, lipoxygenase, COXs and lipopolysaccharides-induced secretion of TNF-α and IL-6 in mouse RAW264.7 macrophages. RESULTS: Synthesized compounds effectively inhibited proinflammatory enzymes and cytokines. CONCLUSION: A strong inhibition of secretory phospholipases A2 was exhibited by benzimidazole derivatives with trifluoromethyl and methoxy substitutions at position 4 of attached phenyl, whereas compound 8 containing pyridine ring substituted with amino group showed very potent 5-lipoxygenase inhibition...
September 21, 2016: Future Medicinal Chemistry
Samuel A McKie
The sheer molecular scale of the ribosome is intimidating to the traditional drug designer. By analyzing the ribosome as a series of 12 key target sites, this review seeks to make the ribosome ligand design process more manageable. Analysis of recently evaluated ribosomal structures, particularly those with bound antibiotics, indicates where the ligand target sites are located. This review employs current research data to map antibiotic binding across the ribosome. A number of neighboring ligand-binding sites are often contiguous and can be combined...
September 21, 2016: Future Medicinal Chemistry
Jürgen Bajorath, John Overington, Jeremy L Jenkins, Pat Walters
No abstract text is available yet for this article.
September 21, 2016: Future Medicinal Chemistry
Gerald Maggiora
No abstract text is available yet for this article.
September 21, 2016: Future Medicinal Chemistry
Sébastien G Gouin
No abstract text is available yet for this article.
September 21, 2016: Future Medicinal Chemistry
Giovanna Zinzalla
No abstract text is available yet for this article.
September 21, 2016: Future Medicinal Chemistry
Tatiana Johnston, Gabriel Lambert Hendricks, Steven Shen, Roy Fangxing Chen, Bumsup Kwon, Michael John Kelso, Wooseong Kim, Beth Burgwyn Fuchs, Eleftherios Mylonakis
AIM: Increasing antimicrobial resistance has compromised the effectiveness of many antibiotics, including those used to treat staphylococcal infections like methicillin-resistant Staphylococcus aureus. The development of combination therapies, where antimicrobial agents are used with compounds that inhibit resistance pathways is a promising strategy. Results/methodology: The Raf kinase inhibitor GW5074 exhibited selective in vitro activity against Gram-positive bacteria, including clinical isolates of S...
September 21, 2016: Future Medicinal Chemistry
Steven L Dixon, Jianxin Duan, Ethan Smith, Christopher D Von Bargen, Woody Sherman, Matthew P Repasky
AIM: We introduce AutoQSAR, an automated machine-learning application to build, validate and deploy QSAR models. METHODOLOGY/RESULTS: The process of descriptor generation, feature selection and the creation of a large number of QSAR models has been automated into a single workflow within AutoQSAR. The models are built using a variety of machine-learning methods, and each model is scored using a novel approach. Effectiveness of the method is demonstrated through comparison with literature QSAR models using identical datasets for six end points: protein-ligand binding affinity, solubility, blood-brain barrier permeability, carcinogenicity, mutagenicity and bioaccumulation in fish...
September 19, 2016: Future Medicinal Chemistry
Shada J Alabed, Mohammad Khanfar, Mutasem O Taha
AIM: FGFR-1 is an oncogenic kinase involved in several cancers. FGFR1-specific inhibitors have shown promising results against several human cancers prompting us to model this interesting target. Toward the end, we implemented elaborate ligand-based and structure-based computational workflows to explore the pharmacophoric requirements for potent FGFR-1 inhibitors. Results & methodology: Structure-based and ligand-based modeling applied on 59 diverse FGFR-1 inhibitors yielded novel pharmacophore and quantitative structure-activity relationship models that were used to scan the National Cancer Institute's structural database for novel leads...
September 19, 2016: Future Medicinal Chemistry
David R Hall, Istvan J Enyedy
AIM: Virtual screening selects compounds that resemble a known modulator or compounds that fit into the binding site of a target protein. Computational solvent mapping defines important chemical features for binding to a target protein. Results/methodology: We have tested the ability to use solvent mapping for generating a 'fake' ligand that is a negative image of the binding site. We used this fake ligand as a query for the program ROCS and to define the search space of the docking programs FRED and HYBRID...
September 15, 2016: Future Medicinal Chemistry
Fabiana Caporuscio, Giulio Rastelli
Structural plasticity is an intrinsic property of proteins that allows each gene product to accomplish its tasks in a strictly regulated manner at a precise time and cellular location. Moreover, protein motions allow protein-ligand and protein-protein recognition. The knowledge of the conformational ensemble that a drug target populates may be crucial for the design of small molecules that can differently modulate its function. X-ray crystallography and NMR have endlessly provided snapshots of protein states...
September 15, 2016: Future Medicinal Chemistry
Noé Sturm, Didier Rognan, Ronald J Quinn, Esther Kellenberger
AIM: We question the level of detail required in protein 3D-representation to detect site similarity which is relevant for polypharmacology prediction. RESULTS: We modified the in-house program SiteAlign to replace generic pharmacophoric descriptors of cavity-lining amino acids by descriptors accounting for solvent exposure. Benchmarking the novel, atom-based, method (SiteAlign2) revealed no global improvement of performance. However, in the rare cases of no sequence or global structure similarities between the compared proteins, SiteAlign2 was more successful if backbone atoms are key determinants of ligand binding...
September 15, 2016: Future Medicinal Chemistry
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