Abstract:
:Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDArequired procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure-activity relationship (QSAR) models for hERG blockage using the largest publicly available dataset of 11,958 compounds from the ChEMBL database. The models have been developed and validated according to OECD guidelines using four types of descriptors and four different machine-learning techniques. The classification accuracies discriminating blockers from non-blockers were as high as 0.83-0.93 on external set. Model interpretation revealed several SAR rules, which can guide structural optimization of some hERG blockers into non-blockers. We have also applied the generated models for screening the World Drug Index (WDI) database and identify putative hERG blockers and non-blockers among currently marketed drugs. The developed models can reliably identify blockers and non-blockers, which could be useful for the scientific community. A freely accessible web server has been developed allowing users to identify putative hERG blockers and non-blockers in chemical libraries of their interest (http://labmol.farmacia.ufg.br/predherg).
journal_name
Curr Top Med Chemjournal_title
Current topics in medicinal chemistryauthors
Braga RC,Alves VM,Silva MF,Muratov E,Fourches D,Tropsha A,Andrade CHdoi
10.2174/1568026614666140506124442subject
Has Abstractpub_date
2014-01-01 00:00:00pages
1399-415issue
11eissn
1568-0266issn
1873-4294pii
CTMC-EPUB-60387journal_volume
14pub_type
杂志文章abstract::Computational toxicity modeling can have significant impact in the drug discovery process, especially when utilized as a sentinel filter for common drug safety liabilities, such as mutagenicity, carcinogenicity and teratogenicity. This review will focus on the strengths and limitations of the current computational mod...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026013395074
更新日期:2001-09-01 00:00:00
abstract::Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate Dehydrogenase Kinase (PDK) is a gatekeeper en...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026618666180523105756
更新日期:2018-01-01 00:00:00
abstract::Biomarkers in the clinical oncology field can have tremendous therapeutic impact especially if the marker is detected before clinical symptoms. This impact can be extended to the evaluation of clinical oncology treatments allowing evaluation of potential compounds to determine their efficacy in the disease treatment. ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802605774297074
更新日期:2005-01-01 00:00:00
abstract::Screening and identifying a disease-specific novel drug target is the first step towards a rational drug designing approach. Due to the advent of high throughput data generation techniques, the protein search space has now exceeded 24,500 human protein coding genes, which encodes approximately 1804proteins. This work ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026618666180719160922
更新日期:2018-01-01 00:00:00
abstract::The knowledge about to which biomolecules a small molecule binds is highly valuable in the drug development process. Although analytical methods to dissect ligand-binding proteome have made substantial progress in the past decades, it is generally too costly, if not infeasible, to know where a small molecule binds at ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802612804547362
更新日期:2012-01-01 00:00:00
abstract::Transient Receptor Potential (TRP) cation channels participate in several processes of vital importance in cell and organism physiology, and have been demonstrated to participate in the detection of sensory stimuli. The thermo TRP's reviewed: TRPV1 (vanilloid 1), TRPM8 (melastatin 8) and TRPA1 (ankyrin-like 1) are kno...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611796904870
更新日期:2011-01-01 00:00:00
abstract::Integrating physicochemical, drug metabolism, pharmacokinetics, ADME, and toxicity assays into drug discovery in order to reduce the attrition rates in clinical development is reviewed. The review is organized around three main decision points used in discovery including hit generation, lead optimization and final can...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802609789630929
更新日期:2009-01-01 00:00:00
abstract::Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs but their use is hampered by gastrointestinal side effects. Cyclo-oxygenase Inhibitor Nitric Oxide Donors (CINODs) are a new class of anti-inflammatory and analgesic drugs generated by adding a nitric oxide generating moiety to the parent NSAID via a...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802607779941350
更新日期:2007-01-01 00:00:00
abstract:BACKGROUND:Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026619666191019105349
更新日期:2020-01-01 00:00:00
abstract::Four compounds (isoquercitrin, myricetin-3-O-glucoside, catechin and gallocatechin) were isolated from lyophilized aqueous extract of Schizolobium parahyba leaves by chromatography on Sephadex LH-20, followed by semipreparative HPLC using a C-18 column, and identified by 1H and 13C NMR. The compounds were then, tested...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/156802611797633438
更新日期:2011-01-01 00:00:00
abstract::The discovery of small molecule melanin concentrating hormone receptor (MHCr1) antagonists as novel therapeutic agents has been widely pursued across the pharmaceutical industry. While multiple chemotypes of small molecule MCHr1 antagonists have been identified and shown to induce weight loss in rodent models of obesi...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802608785700052
更新日期:2008-01-01 00:00:00
abstract:BACKGROUND:Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. OBJECTIVE:That is why we designed twenty-two analogues of a dual AChEBuChE salicylanilide inhibitor, ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026620666200819154722
更新日期:2020-01-01 00:00:00
abstract::The sol-gel process provides a robust and versatile technology for the immobilization of biologicals. A wide range of inorganic, composites and hybrid materials can be prepared to encapsulate molecular drugs, proteins, antibodies/antigens, enzymes, nucleic acids, prokaryotic and eukaryotic cells into bulk gels, partic...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026614666141229112734
更新日期:2015-01-01 00:00:00
abstract::Phyllanthus amarus is a medicinal herb used in traditional Indian medicine for liver disorders. Several researches also show that it acts primarily in the liver, but the molecules were unidentified for liver protective activity. This study was to determine whether the lignans isolated from P. amarus attenuates the D-g...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026614666140324130047
更新日期:2014-01-01 00:00:00
abstract:INTRODUCTION:Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. METHODS:A literature search was conducted using Google Scho...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026618666181115093136
更新日期:2018-01-01 00:00:00
abstract::Modulation of the androgen receptor has the potential to be an effective treatment for hypogonadism, andropause, and associated conditions such as sarcopenia, osteoporosis, benign prostatic hyperplasia, and sexual dysfunction. Side effects associated with classical anabolic steroid treatments have driven the quest for...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802606776173456
更新日期:2006-01-01 00:00:00
abstract::Although bioactivation is a well-documented process and the role of active metabolites in the drug discovery field has long been recognized, drug metabolites are usually ignored in virtual screening campaigns oriented to drug repositioning. The present article discusses different issues related to overlooking of the a...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026616666160216155043
更新日期:2016-01-01 00:00:00
abstract:BACKGROUND:Antimicrobial research is being focused to look for more effective therapeutics against antibiotic-resistant infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In this direction, antimicrobial peptides (AMP) appear as promising tool. OBJECTIVES:This study evaluated the antimicrobial ac...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
doi:10.2174/1568026618666181022140348
更新日期:2018-01-01 00:00:00
abstract::Degenerative diseases are becoming more common with increasing life expectancy of the human population. The 20th century faced a progressive demographic change in the industrialized world, followed by identical trends in population aging in Asia, Africa, and Middle and South America. A significant increase in chronic ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026618666171215094029
更新日期:2017-01-01 00:00:00
abstract::A substantial number of antimicrobial agents target some activity of the bacterial ribosome for inhibition. Mechanistic studies and recent structural investigations of the ribosome have identified the binding sites and presumed mechanism of inhibitory activity for some compounds. A second target for many of these anti...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026033452186
更新日期:2003-01-01 00:00:00
abstract::The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimer's disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endog...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611794072605
更新日期:2011-01-01 00:00:00
abstract::This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) require...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026053544588
更新日期:2005-01-01 00:00:00
abstract::Leukocytes and lung structural cells contribute to the pathophysiology of asthma through the production of numerous mediators including serine proteases. Such proteases include mast cell tryptase and chymase; neutrophil elastase, cathepsin G and myeloblastin (proteinase 3); bronchial epithelial cell-derived transmembr...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802606776287054
更新日期:2006-01-01 00:00:00
abstract::Target-Related Affinity Profiling (TRAP) is a computational drug discovery technology that is based on 'affinity fingerprints', which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026053828394
更新日期:2005-01-01 00:00:00
abstract::The Rho family small GTPases of the Ras superfamily play key roles in regulating diverse signaling pathways that control a myriad of fundamental cellular processes such as cytoskeletal dynamics, cell cycle progression, gene expression, cell polarity, migration and cell transformation. The Rho GTPases cycle between an ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/156802611798281357
更新日期:2011-12-01 00:00:00
abstract::Literature on magnetic fields (MF) and gene expression, as well as on DNA damage, supports the hypothesis that electromagnetic energy may act at atomic level influencing genetic stability. According to quantum physics, MF act on the interconversion of singlet and triplet spin states, and therefore on genetic instabili...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026615666150225104217
更新日期:2015-01-01 00:00:00
abstract::The chemical versatility of the indole nucleus still inspires the pharmaceutical research to develop innovative suitable indole based drugs. The present work is an overview of the use and application of indole molecule based derivatives, as possible treatment in the main Oxidative Stress related diseases, such as card...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026614666141203142926
更新日期:2014-01-01 00:00:00
abstract::Histone deacetylases (HDACs) have recently emerged as key elements in epigenetic control of gene expression. Due to the implication of HDACs in a variety of diseases ranging from cancer to neurodegenerative disorder, HDAC inhibitors have received increased attention in recent years. Over the last few decades, a myriad...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026615666141208105614
更新日期:2015-01-01 00:00:00
abstract::Rhodiola as one of traditional medicines has been used for clinical treatments due to its strong antioxidant properties. Phytochemical analysis revealed the presence of flavonoids, phenylpropanoids, phenylethanol/benzyl alcohol derivatives, cyanogenic glycosides and terpenoids. The bioactive compounds had been demonst...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026617666161116141334
更新日期:2017-01-01 00:00:00
abstract::Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects largely synovial joints. It has been postulated that activated autoreactive CD4 T cells play a key role in triggering and/or maintaining the chronic inflammatory process in RA. Dendritic cells (DCs) are antigen-presenting cells that ac...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
doi:10.2174/1568026611313060004
更新日期:2013-01-01 00:00:00