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drug target disease predict

Saurabh Sharma, Suniti Yadav, Ketaki Chandiok, Radhey Shyam Sharma, Vandana Mishra, Kallur Nava Saraswathy
Background: Metabolic syndrome (MeS), a constellation of metabolic adversities, and history of miscarriage make women at a higher risk for cardiovascular diseases (CVDs). However, molecular evidence indicating a link between the two phenotypes (history of miscarriage and MeS) among women would offer an opportunity to predict the risk factor for CVDs at an early stage. Thus, the present retrospective study attempts to identify the proteins signatures (if any) to understand the connection between the history of miscarriage and MeS...
2019: PeerJ
Shannon G Murphy, Laura Alvarez, Myfanwy C Adams, Shuning Liu, Joshua S Chappie, Felipe Cava, Tobias Dörr
The cell wall is a strong, yet flexible, meshwork of peptidoglycan (PG) that gives a bacterium structural integrity. To accommodate a growing cell, the wall is remodeled by both PG synthesis and degradation. Vibrio cholerae encodes a group of three nearly identical zinc-dependent endopeptidases (EPs) that are predicted to hydrolyze PG to facilitate cell growth. Two of these (ShyA and ShyC) are conditionally essential housekeeping EPs, while the third (ShyB) is not expressed under standard laboratory conditions...
February 19, 2019: MBio
Hanan M Ragab, Mohamed Teleb, Hassan R Haidar, Noha Gouda
In search of potent acetyl cholinesterase inhibitors with low hepatotoxicity for the treatment of Alzheimer's disease, introduction of a chloro substitution to tacrine and some of its analogs has proven to be beneficial in maintaining or potentiating the cholinesterase inhibitory activity. Furthermore, it was found to be able to reduce the hepatotoxicity of the synthesized compounds, which is the main target of the study. Accordingly, a series of new 4-(chlorophenyl)tetrahydroquinoline derivatives, was synthesized and characterized...
February 14, 2019: Bioorganic Chemistry
Kimberley M Zorn, Thomas R Lane, Daniel P Russo, Alex M Clark, Vadim Makarov, Sean Ekins
The human immunodeficiency virus (HIV) causes over a million deaths every year and has a huge economic impact in many countries. The first class of drugs approved were nucleoside reverse transcriptase inhibitors. A newer generation of reverse transcriptase inhibitors have become susceptible to drug resistant strains of HIV, and hence alternatives are urgently needed. We have recently pioneered the use of Bayesian machine learning to generate models with public data to identify new compounds for testing against different disease targets...
February 19, 2019: Molecular Pharmaceutics
Jarem J Edwards, Annie Tasker, Ines Silva, Camelia Quek, Marcel Batten, Angela L Ferguson, Ruth Allen, Benjamin Michael Allanson, Robyn Pm Saw, John F Thompson, Alexander M Menzies, Umaimainthan Palendira, James S Wilmott, Georgina Long, Richard A Scolyer
BACKGROUND: Immunotherapies targeting co-stimulating and co-inhibitory checkpoint receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known about the relative abundance, co-expression, and immune cells enriched for each specific drug target, limiting understanding of the biological basis of potential treatment outcomes and development of predictive biomarkers for personalized immunotherapy. AIMS: We sought to assess the abundance of checkpoint receptors during melanoma disease progression, and identify immune cells enriched for them...
February 18, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Raunak Shrestha, Noushin Nabavi, Yen-Yi Lin, Fan Mo, Shawn Anderson, Stanislav Volik, Hans H Adomat, Dong Lin, Hui Xue, Xin Dong, Robert Shukin, Robert H Bell, Brian McConeghy, Anne Haegert, Sonal Brahmbhatt, Estelle Li, Htoo Zarni Oo, Antonio Hurtado-Coll, Ladan Fazli, Joshua Zhou, Yarrow McConnell, Andrea McCart, Andrew Lowy, Gregg B Morin, Tianhui Chen, Mads Daugaard, S Cenk Sahinalp, Faraz Hach, Stephane Le Bihan, Martin E Gleave, Yuzhuo Wang, Andrew Churg, Colin C Collins
BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation...
February 18, 2019: Genome Medicine
Adam S Darwich, Howard J Burt, Amin Rostami-Hodjegan
Physiologically-based pharmacokinetic (PBPK) models provide a framework for in vitro-in vivo extrapolation of metabolic drug clearance. Many of the concepts in PBPK can have consequential impact on more mechanistic systems pharmacology models. In the gut wall, turnover of enzymes and enterocytes are typically lumped into one rate constant that describes the time dependent enzyme activity. This assumption may influence predictability of any sustained and dynamic effects such as mechanism-based inhibition (MBI), particularly when considering translation from healthy to gut disease...
February 15, 2019: European Journal of Pharmaceutical Sciences
Nuria Codina, David Hilton, Cheng Zhang, Nesrine Chakroun, Shahina S Ahmad, Stephen J Perkins, Paul A Dalby
Protein aggregation is the underlying cause of many diseases, and also limits the usefulness of many natural and engineered proteins in biotechnology. Better mechanistic understanding and characterization of aggregation-prone states, is needed to guide protein engineering, formulation, and drug-targeting strategies that prevent aggregation. While several final aggregated states - notably amyloids - have been characterized structurally, very little is known about the native structural conformers that initiate aggregation...
February 15, 2019: Journal of Molecular Biology
Xingyi Li, Wenkai Li, Min Zeng, Ruiqing Zheng, Min Li
Genes that are thought to be critical for the survival of organisms or cells are called essential genes. The prediction of essential genes and their products (essential proteins) is of great value in exploring the mechanism of complex diseases, the study of the minimal required genome for living cells and the development of new drug targets. As laboratory methods are often complicated, costly and time-consuming, a great many of computational methods have been proposed to identify essential genes/proteins from the perspective of the network level with the in-depth understanding of network biology and the rapid development of biotechnologies...
February 18, 2019: Briefings in Bioinformatics
Xiao-Long Shi, Jing-De Wu, Ping Liu, Zhao-Peng Liu
To target the multi-facets of Alzheimer's disease (AD), a series of novel GSK-3β inhibitors containing the 2,3-diaminopyridine moiety were designed and synthesized. The amide derivatives 5a-f showed moderate potency against GSK-3β with weak Cu2+ , Zn2+ and Al3+ chelating ability. The imine derivatives 9a, 9b and 9e were potent GSK-3β inhibitors and selective Cu2+ and Al3+ chelators. The 1,2-diamine derivatives 10a-e were strong metal-chelators, but decreased or lost their GSK-3β inhibitory potency. In vitro, compounds 9a, 9b and 9e, especially 9b, exhibited good Cu2+ -induced Aβ aggregation inhibition, Cu2+ -Aβ complex disaggregation, ROS formation inhibition, and antioxidant activities...
February 8, 2019: European Journal of Medicinal Chemistry
Ehab D AlFadly, Perihan A Elzahhar, Anna Tramarin, Salwa Elkazaz, Hossam Shaltout, Marwa M Abu-Serie, Jana Janockova, Ondrej Soukup, Doaa A Ghareeb, Ahmed F El-Yazbi, Rim W Rafeh, Nour-Mounira Z Bakkar, Firas Kobeissy, Isabel Iriepa, Ignacio Moraleda, Manal N S Saudi, Manuela Bartolini, Ahmed S F Belal
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition)...
February 8, 2019: European Journal of Medicinal Chemistry
Vaishnavi Sambandam, Mitchell J Frederick, Li Shen, Pan Tong, Xiayu Rao, Shaohua Peng, Ratnakar Singh, Tuhina Mazumdar, Chenfei Huang, Qiuli Li, Curtis R Pickering, Jeffrey N Myers, Jing Wang, Faye M Johnson
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function...
February 15, 2019: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dominic H Banda, Paula M Perin, Richard J P Brown, Daniel Todt, Wladimir Solodenko, Patrick Hoffmeyer, Kamlesh Kumar Sahu, Michael Houghton, Philip Meuleman, Rolf Müller, Andreas Kirschning, Thomas Pietschmann
BACKGROUND & AIMS: Hepatitis C virus infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors representing candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. METHODS: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations...
February 12, 2019: Journal of Hepatology
Jian Xu, Yan Su, Aoshuang Xu, Fengjuan Fan, Shidai Mu, Lei Chen, Zhangbo Chu, Bo Zhang, Haifan Huang, Jiasi Zhang, Jun Deng, Lisha Ai, Chunyan Sun, Yu Hu
Inherent or acquired resistance to chemotherapeutic drugs is still an obstacle for the treatment of multiple myeloma (MM). MicroRNA dysregulation is related to the development of chemoresistance in cancers. However, its role in chemoresistance of MM is largely unknown. Here we demonstrated that miR-221/222 were upregulated in plasma cells from patients with MM, especially those with relapsed or refractory disease. Moreover, expression levels of miR-221/222 were inversely correlated with dexamethasone (Dex) sensitivity of human MM cell lines...
January 24, 2019: Molecular Therapy: the Journal of the American Society of Gene Therapy
Wei Wu, Ke He, Qian Guo, Jingdi Chen, Mengjiao Zhang, Kai Huang, Dongmei Yang, Lu Wu, Yunchao Deng, Xu Luo, Honggang Yu, Qianshan Ding, Guoan Xiang
In this study, microarray data analysis, real-time quantitative PCR and immunohistochemistry were used to detect the expression levels of SSRP1 in colorectal cancer (CRC) tissue and in corresponding normal tissue. The association between structure-specific recognition protein 1 (SSRP1) expression and patient prognosis was examined by Kaplan-Meier analysis. SSRP1 was knocked down and overexpressed in CRC cell lines, and its effects on proliferation, cell cycling, migration, invasion, cellular energy metabolism, apoptosis, chemotherapeutic drug sensitivity and cell phenotype-related molecules were assessed...
February 14, 2019: Journal of Cellular and Molecular Medicine
Tianyun Wang, Lei Chen, Xian Zhao
AIM AND OBJECTIVE: There are several diseases having a complicated mechanism. For such complicated diseases, a single drug cannot treat them very well because these diseases always involve several targets and single targeted drugs cannot modulate these targets simultaneously. Drug combination is an effective way to treat such diseases. However, determination of effective drug combinations is time- and cost-consuming via traditional methods. It is urgent to build quick and cheap methods in this regard...
December 26, 2018: Combinatorial Chemistry & High Throughput Screening
Andrea Miró-Canturri, Rafael Ayerbe-Algaba, Younes Smani
Multidrug-resistant (MDR) pathogens pose a well-recognized global health threat that demands effective solutions; the situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the ten million deaths predicted to occur by 2050 as a result of MDR bacteria. The repurposing of drugs as therapeutic alternatives for infections has recently gained renewed interest...
2019: Frontiers in Microbiology
Bertha A Brodin, Krister Wennerberg, Elisabet Lidbrink, Otte Brosjö, Swapnil Potdar, Jennifer N Wilson, Limin Ma, Lotte N Moens, Asle Hesla, Edvin Porovic, Edvin Bernhardsson, Antroula Papakonstantinou, Henrik Bauer, Panagiotis Tsagkozis, Karin von Sivers, Johan Wejde, Päivi Östling, Olli Kallioniemi, Christina Linder Stragliotto
BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs...
February 12, 2019: British Journal of Cancer
Pradeep Paudel, Su Hui Seong, Sangwook Wu, Suhyun Park, Hyun Ah Jung, Jae Sue Choi
The G protein-coupled receptor (GPCR) family of proteins comprises signaling proteins that mediate cellular responses to various hormones and neurotransmitters, and serves as a prime target for drug discovery. Towards our goal of discovering secondary metabolites from natural sources that can function as neuronal drugs, we evaluated the modulatory effect of eckol on various GPCRs via cell-based functional assays. In addition, we conducted in silico predictions to obtain molecular insights into the functional effects of eckol...
February 10, 2019: Marine Drugs
Reaz Uddin, Noor-Ul-Ain Zahra, Syed Sikander Azam
Tuberculosis (TB) is a major global health challenge. It has been afflicting human for thousands of years and is still severely affecting a huge population. The etiological agent of the disease is Mycobacterium tuberculosis (MTB) that survives in the human host in latent, dormant, and non-replicative state by evading the immune system. It is one of the leading causes of infection related death worldwide. The situation is exacerbated by the massive increase in the resistant strains such as multi-drug resistant TB (MDR-TB) and extensive drug-resistant TB (XDR-TB)...
January 24, 2019: Computational Biology and Chemistry
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