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https://www.readbyqxmd.com/read/27936445/synthesis-and-antifungal-activity-of-novel-indole-replaced-streptochlorin-analogues
#1
Ming-Zhi Zhang, Chen-Yang Jia, Yu-Cheng Gu, Nick Mulholland, Sarah Turner, David Beattie, Wei-Hua Zhang, Guang-Fu Yang, John Clough
Based on examples of the successful applications in drug discovery of bioisosterism, a series of streptochlorin analogues in which indole has been replaced by other heterocycles has been designed and synthesized, as a continuation of our studies aimed at the discovery of novel streptochlorin analogues with improved antifungal activity. Biological testing showed that most of the indole-replaced streptochlorin analogues were inactive, though compound 6f had a broad spectrum of antifungal activity with significant activity against Alternaria solani...
December 2, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27935308/combining-molecular-scaffolds-from-fda-approved-drugs-application-to-drug-discovery
#2
Richard David Taylor, Malcolm MacCoss, Alastair D G Lawson
We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in-silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries...
December 9, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27935197/ring-expansion-approach-to-medium-sized-lactams-and-analysis-of-their-medicinal-lead-like-properties
#3
Laetitia G Baud, Morgan Ann Manning, Helen L Arkless, Thomas C Stephens, William Paul Unsworth
Medium-sized rings are widely considered to be under-represented in biological screening libraries for lead identification in medicinal chemistry. To help address this, a library of medium-sized lactams has been generated using a simple, scalable and versatile ring expansion protocol. Analysis of the library using open access computational tool LLAMA suggests that these lactams and their derivatives have highly promising physicochemical and 3D spatial properties and thus have much potential in drug discovery...
December 9, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27933945/fragment-based-approach-to-the-development-of-an-orally-bioavailable-lactam-inhibitor-of-lipoprotein-associated-phospholipase-a2-lp-pla2
#4
Alison J-A Woolford, Philip J Day, Véronique Bénéton, Valerio Berdini, Joseph E Coyle, Yann Dudit, Pascal Grondin, Pascal Huet, Lydia Y W Lee, Eric S Manas, Rachel L McMenamin, Christopher W Murray, Lee W Page, Vipulkumar K Patel, Florent Potvain, Sharna J Rich, Yingxia Sang, Don O Somers, Lionel Trottet, Zehong Wan, Xiaomin Zhang
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27933808/accurate-modeling-of-scaffold-hopping-transformations-in-drug-discovery
#5
Lingle Wang, Yuqing Deng, Yujie Wu, Byungchan Kim, David N LeBard, Dan Wandschneider, Mike Beachy, Richard A Friesner, Robert Abel
The accurate prediction of protein-ligand binding free energies remains a significant challenge of central importance in computational biophysics and structure-based drug design. Multiple recent advances including the development of greatly improved protein and ligand molecular mechanics force fields, more efficient enhanced sampling methods, and low-cost powerful GPU computing clusters have enabled accurate and reliable predictions of relative protein-ligand binding free energies through the free energy perturbation (FEP) methods...
December 9, 2016: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/27933783/a-comprehensive-computational-analysis-for-the-binding-modes-of-hepatitis-c-virus-ns5a-inhibitors-the-question-of-symmetry
#6
Marawan Ahmed, Abhishek Pal, Michael Houghton, Khaled Barakat
Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete...
November 11, 2016: ACS Infectious Diseases
https://www.readbyqxmd.com/read/27933725/cellular-engineering-for-therapeutic-protein-production-product-quality-host-modification-and-process-improvement
#7
REVIEW
Evan Wells, Anne Skaja Robinson
Recombinant proteins offer many therapeutic advantages unavailable in traditional small molecule drugs, but the need for cellular versus chemical synthesis complicates production. Avenues for producing therapeutic biologics are continuously expanding, and developments in biochemistry, cell biology, and bioengineering fuel new discoveries that promise safer, more efficient, and cheaper drugs for consumers. Numerous approaches to express recombinant proteins exist, but Escherichia coli, Saccharomyces cerevisiae, and mammalian systems (e...
December 9, 2016: Biotechnology Journal
https://www.readbyqxmd.com/read/27933602/fish-tales-the-use-of-zebrafish-xenograft-human-cancer-cell-models
#8
REVIEW
Yvette Drabsch, B Ewa Snaar-Jagalska, Peter Ten Dijke
Advances in scientific techniques have provided researchers with exceptional new opportunities to identify and monitor changes between different cancer types, during different stages of progression, between individual tumor cells and in the surrounding stroma. The wealth of information that can be obtained from new scientific techniques places additional requirements on the conventional cancer models. New models that could be used to rapidly access the (potential) functional importance of newly identified (epi)genetic and proteomic changes and test the efficacy on emerging (combinatorial) therapies are desperately required...
December 9, 2016: Histology and Histopathology
https://www.readbyqxmd.com/read/27933485/fluid-based-biomarkers-for-amyotrophic-lateral-sclerosis
#9
REVIEW
Lucas T Vu, Robert Bowser
Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients...
December 8, 2016: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
https://www.readbyqxmd.com/read/27933367/antipsychotic-inductors-of-brain-hypothermia-and-torpor-like-states-perspectives-of-application
#10
REVIEW
Yury S Tarahovsky, Irina S Fadeeva, Natalia P Komelina, Maxim O Khrenov, Nadezhda M Zakharova
Hypothermia and hypometabolism (hypometabothermia) normally observed during natural hibernation and torpor, allow animals to protect their body and brain against the damaging effects of adverse environment. A similar state of hypothermia can be achieved under artificial conditions through physical cooling or pharmacological effects directed at suppression of metabolism and the processes of thermoregulation. In these conditions called torpor-like states, the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases...
December 8, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27932801/dna-encoded-chemistry-enabling-the-deeper-sampling-of-chemical-space
#11
Robert A Goodnow, Christoph E Dumelin, Anthony D Keefe
DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces...
December 9, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27932582/translational-safety-genetics-leveraging-genetic-variation-for-enhanced-safety-assessment
#12
Priyasma Bhoumik, Alberto Del Rio-Espinola, Florian Hahne, Jonathan Moggs, Olivier Grenet
The emerging field of translational safety genetics is providing new opportunities to enhance drug discovery and development. Genetic variation in therapeutic drug targets, off-target interactors and relevant drug metabolism/disposition pathways can contribute to diverse drug pharmacologic and toxicologic responses between different animal species, strains and geographic origins. Recent advances in the sequencing of rodent, canine, nonhuman primate, and minipig genomes have dramatically improved the ability to select the most appropriate animal species for preclinical drug toxicity studies based on genotypic characterization of drug targets/pathways and drug metabolism and/or disposition, thus avoiding inconclusive or misleading animal studies, consistent with the principles of the 3Rs (replacement, reduction and refinement)...
December 8, 2016: Toxicologic Pathology
https://www.readbyqxmd.com/read/27932461/structural-characterization-and-ligand-inhibitor-identification-provide-functional-insights-into-the-mycobacterium-tuberculosis-cytochrome-p450-cyp126a1
#13
Jude T Chenge, Duyet Van Le, Shalini Swami, Kirsty J McLean, Madeline E Kavanagh, Anthony G Coyne, Stephen E J Rigby, Myles R Cheesman, Hazel M Girvan, Colin W Levy, Bernd Rupp, Jens P von Kries, Chris Abell, David Leys, Andrew W Munro
The Mycobacterium tuberculosis (Mtb) H37Rv genome encodes 20 cytochromes P450, including P450s crucial to infection and bacterial viability. Many Mtb P450s remain uncharacterized, suggesting their further analysis may provide new insights into Mtb metabolic processes and new targets for drug discovery. CYP126A1 is representative of a P450 family widely distributed in mycobacteria and other bacteria. Here we explore the biochemical and structural properties of CYP126A1, including its interactions with new chemical ligands...
December 8, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27930943/analyzing-biased-responses-of-gpcr-ligands
#14
REVIEW
Besma Benredjem, Paul Dallaire, Graciela Pineyro
G protein-coupled receptors (GPCRs) are valuable targets for drug discovery. They exist in interconverting states differentially stabilized by diverse signaling partners. A ligand's capacity to distinguish among receptors associated with different partners is the basis of bias. This feature of GPCR signaling may allow development of ligands which specifically modulate effectors supporting desired actions. However, bias is time-dependent and cell-dependent such that in vitro bias may not predict bias displayed in vivo...
December 5, 2016: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/27930812/assessing-2d-electrophoretic-mobility-spectroscopy-2d-mosy-for-analytical-applications
#15
Yuan Fang, Pavel V Yushmanov, István Furó
Electrophoretic displacement of charged entities phase modulates the spectrum acquired in electrophoretic NMR experiments and this modulation can be presented via 2D FT transformation as 2D MOSY (MObility SpectroscopY) spectra. We compare in various mixed solutions the chemical selectivity provided by 2D MOSY spectra to that provided by 2D DOSY (Diffusion Ordered SpectroscopY) spectra and demonstrate, under the conditions explored, a superior performance of the former method. 2D MOSY compares also favourably to closely related LC-NMR methods...
December 8, 2016: Magnetic Resonance in Chemistry: MRC
https://www.readbyqxmd.com/read/27928949/from-leflunomide-to-teriflunomide-drug-development-and-immunosuppressive-oral-drugs-in-the-treatment-of-multiple-sclerosis
#16
Lilian Aly, Bernhard Hemmer, Thomas Korn
Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, the increased number of approved substances and the possibility of an oral availability of some immunomodulators improve the therapeutic repertory and increase patient satisfaction and compliance. Teriflunomide is indicated as first line oral disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Its immunosuppressive capacity results from an inhibition of de novo pyrimidine synthesis in rapidly proliferating lymphocytes...
December 8, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27928884/building-proteomic-tool-boxes-to-monitor-mhc-class-i-and-class-ii-peptides
#17
REVIEW
Frances-Rose Schumacher, Lélia Delamarre, Suchit Jhunjhunwala, Zora Modrusan, Qui T Phung, Joshua E Elias, Jennie R Lill
Major histocompatibility complex Class I (MHCI) and Class II (MHCII) presented peptides powerfully modulate T cell immunity and play a vital role in generating effective anti-tumor and anti-viral immune responses in mammals. Characterizing these MHCI or MHCII presented peptides can help generate therapeutic treatments, afford information on T cell mediated biomarkers, provide insight into disease progression, and reduce adverse anti-drug side effects from engineered biotherapeutics. Here, we explore the tools and techniques commonly employed to discover both MHCI and MHCII presented peptides...
December 8, 2016: Proteomics
https://www.readbyqxmd.com/read/27928026/azd3759-a-bbb-penetrating-egfr-inhibitor-for-the-treatment-of-egfr-mutant-nsclc-with-cns-metastases
#18
Zhenfan Yang, Qiuli Guo, Yingchun Wang, Kan Chen, Lin Zhang, Ziqiang Cheng, Yanping Xu, Xiaolu Yin, Yu Bai, Sarit Rabbie, Dong-Wan Kim, Myung-Ju Ahn, James Chih-Hsin Yang, Xiaolin Zhang
Non-small-cell lung cancer patients with activating mutations in epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitor (TKI) treatment. Nevertheless, patients often develop central nervous system (CNS) metastases during treatment, even when their extracranial tumors are still under control. In the absence of effective options, much higher doses of EGFR TKIs have been attempted clinically, with the goal of achieving high enough drug concentrations within the CNS. Although limited tumor responses have been observed with this approach, the toxicities outside the CNS have been too high to tolerate...
December 7, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27927696/gene-expression-signature-a-powerful-approach-for-drug-discovery-in-diabetes
#19
Smithamol Sithara, Tamsyn Crowley, Ken Walder, Kathryn Aston-Mourney
Type 2 diabetes (T2D) is increasing in prevalence at an alarming rate around the world. Much effort has gone into the discovery and design of anti-diabetic drugs, however those already available are unable to combat the underlying causes of the disease and instead only moderate the symptoms. The reason for this is that T2D is a complex disease and attempts to target one biological pathway are insufficient to combat the full extent of the disease. Additionally, the underlying pathophysiology of this disease is yet to be fully elucidated making it difficult to design drugs that target the mechanisms involved...
December 7, 2016: Journal of Endocrinology
https://www.readbyqxmd.com/read/27927046/advances-in-chemical-pharmacotherapy-to-manage-advanced-breast-cancer
#20
Andrea Gombos, Ahmad Awada
Advanced breast cancer is still incurable. However, patients diagnosed with this fatal disease live longer. The selection of systemic therapy is mainly based on molecular subtype. The aim of management in these patients is to not only improve outcome, but also to maintain quality of life. Areas covered: In this paper we focus on available treatments and drugs under late development in the three main subtypes of breast cancer: luminal (hormone receptor positive), HER2 positive and triple negative disease. Main advances during the last years have been made in the treatment of HER2 positive breast cancer with the approval of several new targeted agents...
December 7, 2016: Expert Opinion on Pharmacotherapy
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