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https://www.readbyqxmd.com/read/28324785/-ub006-a-new-fatty-acid-synthase-inhibitor-and-cytotoxic-agent-without-anorexic-side-effects
#1
Kamil Makowski, Joan Francesc Mir, Paula Mera, Xavier Ariza, Guillermina Asins, Fausto G Hegardt, Laura Herrero, Jordi García, Dolors Serra
C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately...
March 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28323403/discovery-of-potent-antiallodynic-agents-for-neuropathic-pain-targeting-p2x3-receptors
#2
Young-Hwan Jung, Yong-Chul Kim, Yeo Ok Kim, Hai Lin, Joong-Heui Cho, Jin-Hee Park, So-Deok Lee, Jinsu Bae, Koon Mook Kang, Yoon Gyoon Kim, Ae Nim Pae, Hyojin Ko, Chul-Seung Park, Myung Ha Yoon
Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28320091/animal-models-for-assessing-the-impact-of-natural-products-on-the-aetiology-and-metabolic-pathophysiology-of-type-2-diabetes
#3
REVIEW
Md Asrafuzzaman, Yingnan Cao, Rizwana Afroz, Danielle Kamato, Susan Gray, Peter J Little
Type 2 diabetes mellitus is a complex and heterogeneous disorder which in its most common manifestation arises from insulin resistance and later insulin insufficiency. Type 2 diabetes is characterised by impaired insulin sensitivity and diagnosed as hyperglycaemia. Because of its cardiovascular consequences, Type 2 diabetes represents one of the world's leading causes of mortality and morbidity. Drug discovery and development are required to produce better ways to prevent, treat and manage diabetes and its complications...
March 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28319812/exploring-sequence-space-harnessing-chemical-and-biological-diversity-towards-new-peptide-leads
#4
REVIEW
Richard Obexer, Louise J Walport, Hiroaki Suga
From their early roots in natural products, peptides now represent an expanding class of novel drugs. Their modular structures make them ideal candidates for pooled library screening approaches. Key technologies for library generation and screening, such as SICLOPPS, phage display and mRNA display, give unparalleled access to tight binding peptides. Through combination with genetic code reprogramming and chemical modifications, access to more natural product-like libraries, spanning non-canonical peptide space, is readily achievable...
March 17, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28319364/a-new-spin-on-antibody-drug-conjugates-trastuzumab-fulvestrant-colloidal-drug-aggregates-target-her2-positive-cells
#5
Ahil N Ganesh, Christopher Mclaughlin, Da Duan, Brian K Shoichet, Molly S Shoichet
While the formation of colloidal aggregates leads to artifacts in early drug discovery, their composition makes them attrac-tive as nanoparticle formulations for targeted drug delivery as the entire nanoparticle is composed of drug. The typical tran-sient stability of colloidal aggregates has inhibited exploiting this property. To overcome this limitation, we investigated a series of proteins to stabilize colloidal aggregates of the chemotherapeutic, fulvestrant, including: bovine serum albumin, a generic human immunoglobulin G, and trastuzumab, a therapeutic anti-human epidermal growth factor receptor 2 anti-body...
March 20, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28318251/molecular-simulation-studies-on-the-binding-selectivity-of-type-i-inhibitors-in-the-complexes-with-ros1-versus-alk
#6
Yuanxin Tian, Yonghuan Yu, Yudong Shen, Hua Wan, Shan Chang, Tingting Zhang, Shanhe Wan, Jiajie Zhang
ROS1 and ALK are promising targets of anti-cancer drugs for non small cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, selective ROS1 inhibitor is relative rarely. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#7
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28315995/ligand-based-virtual-screening-under-partial-shape-constraints
#8
Mathias M von Behren, Matthias Rarey
Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure...
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315121/untangling-the-biology-of-genetic-cardiomyopathies-with-pluripotent-stem-cell-disease-models
#9
REVIEW
Jan W Buikema, Sean M Wu
PURPOSE OF REVIEW: Recently, the discovery of strategies to reprogram somatic cells into induced pluripotent stem (iPS) cells has led to a major paradigm change in developmental and stem cell biology. The application of iPS cells and their cardiac progeny has opened novel directions to study cardiomyopathies at a cellular and molecular level. This review discusses approaches currently undertaken to unravel known inherited cardiomyopathies in a dish. RECENT FINDINGS: With improved efficiency for mutation correction by genome editing, human iPS cells have now provided a platform to untangle the biology of cardiomyopathies...
April 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/28314117/three-dimensional-cell-cultures-in-drug-discovery-and-development
#10
Ye Fang, Richard M Eglen
The past decades have witnessed significant efforts toward the development of three-dimensional (3D) cell cultures as systems that better mimic in vivo physiology. Today, 3D cell cultures are emerging, not only as a new tool in early drug discovery but also as potential therapeutics to treat disease. In this review, we assess leading 3D cell culture technologies and their impact on drug discovery, including spheroids, organoids, scaffolds, hydrogels, organs-on-chips, and 3D bioprinting. We also discuss the implementation of these technologies in compound identification, screening, and development, ranging from disease modeling to assessment of efficacy and safety profiles...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28306360/the-antibiotic-pipeline-reviving-research-and-development-and-speeding-drugs-to-market
#11
Katherine H Luepke, John F Mohr
The combination of growing antimicrobial resistance with a dry pipeline has resulted in infections that can no longer be treated. Specific reasons have led to companies' exit from the antibacterial space, however recent incentives are spurring interest to reinvigorate the pipeline. Areas Covered: This article summarizes the available information on the discovery, developmental, and regulatory challenges in antibacterial development that have led to disinterest in the space, as well as ongoing incentives such as public-private partnerships and streamlined pathways to mend these challenges and bring new antibiotics to patients in need...
March 17, 2017: Expert Review of Anti-infective Therapy
https://www.readbyqxmd.com/read/28303026/strategies-and-challenges-for-the-next-generation-of-antibody-drug-conjugates
#12
REVIEW
Alain Beck, Liliane Goetsch, Charles Dumontet, Nathalie Corvaïa
Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody...
March 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28302029/in-silico-adme-studies-for-new-drug-discovery-from-chemical-compounds-to-chinese-herbal-medicines
#13
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/28302028/quantum-mechanical-qm-calculations-applied-to-admet-drug-prediction-a-review
#14
Edeildo F Silva-Júnior, J X Araújo-Júnior, T M Aquino
The discovery of new drugs is generally considered a long and expensive process, which often leads to molecules with low efficacy and high toxicity, which in many cases can be related to metabolism. In an attempt to reduce these failures and the production costs of a new drug, in silico studies have been used to obtain important information about the behavior of these compounds in the metabolism phases: absorption, distribution, metabolism (or biotransformation) and elimination (or excretion). Quantum Mechanical (QM) calculations are based on Schrödinger's equation can be used to develop models and theoretical parameters able to explain properties observed experimentally...
March 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28301705/reprioritizing-research-activity-for-the-post-antibiotic-era-ethical-legal-and-social-considerations
#15
Spencer Phillips Hey, Aaron S Kesselheim
Many hold that the so-called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research-including clinical trials and regulatory requirements-to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 21st Century Cures Act...
March 2017: Hastings Center Report
https://www.readbyqxmd.com/read/28300771/inhibitors-of-brd4-protein-from-a-marine-derived-fungus-alternaria-sp-nh-f6
#16
Hui Ding, Dashan Zhang, Biao Zhou, Zhongjun Ma
Bromodomains (BRD) are readers of the epigenetic code that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Recently, bromodomain-containing proteins such as BRD4 have been demonstrated to be druggable through the discovery of potent inhibitors. These protein-protein interaction inhibitors have the potential to modulate multiple diseases by their profound anti-inflammatory and antiproliferative effects. In order to explore new BRD4 inhibitors as well as lead compounds for the development of new drugs, the secondary metabolites of Alternaria sp...
March 16, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28300672/discovery-of-three-toxin-peptides-with-kv1-3-channel-and-il-2-cytokine-inhibiting-activities-from-non-buthidae-scorpions-chaerilus-tricostatus-and-chaerilus-tryznai
#17
Li Ding, Jing Chen, Jinbo Hao, Jiahui Zhang, Xuejun Huang, Fangfang Hu, Zheng Wu, Yaru Liu, Wenxin Li, Zhijian Cao, Yingliang Wu, Jian Li, Shan Li, Hongyan Liu, Wenlong Wu, Zongyun Chen
Non-Buthidae venomous scorpions are huge natural sources of toxin peptides; however, only a few studies have been done to understand their toxin peptides. Herein, we describe three new potential immunomodulating toxin peptides, Ctri18, Ctry68 and Ctry2908, from two non-Buthidae scorpions, Chaerilus tricostatus and Chaerilus tryznai. Sequence alignment analyses showed that Ctri18, Ctry68 and Ctry2908 are three new members of the scorpion toxin α-KTx15 subfamily. Electrophysiological experiments showed that Ctri18, Ctry68 and Ctry2908 blocked the Kv1...
March 12, 2017: Peptides
https://www.readbyqxmd.com/read/28300647/heter-lp-a-heterogeneous-label-propagation-algorithm-and-its-application-in-drug-repositioning
#18
Maryam Lotfi Shahreza, Nasser Ghadiri, Seyed Rasoul Mousavi, Jaleh Varshosaz, James R Green
Drug repositioning offers an effective solution to drug discovery, saving both time and resources by finding new indications for existing drugs. Typically, a drug takes effect via its protein targets in the cell. As a result, it is necessary for drug development studies to conduct an investigation into the interrelationships of drugs, protein targets, and diseases. Although previous studies have made a strong case for the effectiveness of integrative network-based methods for predicting these interrelationships, little progress has been achieved in this regard within drug repositioning research...
March 11, 2017: Journal of Biomedical Informatics
https://www.readbyqxmd.com/read/28299357/integrating-functional-genomics-to-accelerate-mechanistic-personalized-medicine
#19
Jeffrey W Tyner
The advent of deep sequencing technologies has resulted in the deciphering of tremendous amounts of genetic information. These data have led to major discoveries, and many anecdotes now exist of individual patients whose clinical outcomes have benefited from novel, genetically guided therapeutic strategies. However, the majority of genetic events in cancer are currently undrugged, leading to a biological gap between understanding of tumor genetic etiology and translation to improved clinical approaches. Functional screening has made tremendous strides in recent years with the development of new experimental approaches to studying ex vivo and in vivo drug sensitivity...
March 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28298557/chemical-approaches-to-targeted-protein-degradation-through-modulation-of-the-ubiquitin-proteasome-pathway
#20
REVIEW
Ian Collins, Hannah Wang, John J Caldwell, Raj Chopra
Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic...
March 15, 2017: Biochemical Journal
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