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https://www.readbyqxmd.com/read/28813151/the-medicinal-and-biological-chemistry-mbc-library-an-efficient-source-on-new-hits
#1
Víctor Sebastián Pérez, Carlos Roca, Mahendra Awale, Jean-Louis Reymond, Ana Martínez, Carmen Gil, Nuria E Campillo
Identification of new hits is one of the biggest challenges in drug discovery. Creating a library of well-characterized drug-like compounds is a key step in this process. Our group has developed an in-house chemical library called Medicinal and Biological Chemistry (MBC) library. This collection has been successfully used to start several medicinal chemistry programs and developed in an accumulation of more than thirty years of experience in drug design and discovery of new drugs for unmet diseases. It contains over 1,000 compounds, mainly heterocyclic scaffolds...
August 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28812273/a-precision-medicine-approach-to-oxytocin%C3%A2-trials
#2
Elissar Andari, Rene Hurlemann, Larry J Young
In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders...
August 16, 2017: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28811659/identification-synthesis-and-biological-activity-of-alkyl-guanidine-oligomers-as-potent-antibacterial-agents
#3
C Zamperini, G Maccari, D Deodato, C Pasero, I D'Agostino, F Orofino, F De Luca, E Dreassi, J D Docquier, M Botta
In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811565/iss-pc-identifying-splicing-sites-via-physical-chemical-properties-using-deep-sparse-auto-encoder
#4
Zhao-Chun Xu, Peng Wang, Wang-Ren Qiu, Xuan Xiao
Gene splicing is one of the most significant biological processes in eukaryotic gene expression, such as RNA splicing, which can cause a pre-mRNA to produce one or more mature messenger RNAs containing the coded information with multiple biological functions. Thus, identifying splicing sites in DNA/RNA sequences is significant for both the bio-medical research and the discovery of new drugs. However, it is expensive and time consuming based only on experimental technique, so new computational methods are needed...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811324/the-transcriptional-program-functional-heterogeneity-and-clinical-targeting-of-mast-cells
#5
REVIEW
Gökhan Cildir, Harshita Pant, Angel F Lopez, Vinay Tergaonkar
Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions...
August 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28811131/assessment-of-translational-risk-in-drug-research-role-of-biomarker-classification-and-mechanism-based-pkpd-concepts
#6
Sandra A G Visser, Tjerk J H Bueters
In 2005, Danhof and coauthors proposed a new biomarker classification in the context of the application of mechanism-based PKPD modeling. They defined the term 'biomarker' as a measure that characterizes a drug-induced response, which is on the causal path between drug administration and clinical outcome. The biomarker classification identified seven categories that provide different insights into the kinetics of drug action, such as target site distribution, target engagement, or into the impact of the drug on physiology or disease...
August 12, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28811111/cell-cultures-in-drug-discovery-and-development-the-need-of-reliable-in-vitro-in-vivo-extrapolation-for-pharmacodynamics-and-pharmacokinetics-assessment
#7
REVIEW
Karol Jaroch, Alina Jaroch, Barbara Bojko
For ethical and cost-related reasons, use of animals for the assessment of mode of action, metabolism and/or toxicity of new drug candidates has been increasingly scrutinized in research and industrial applications. Implementation of the 3 "Rs"(1); rule (Reduction, Replacement, Refinement) through development of in silico or in vitro assays has become an essential element of risk assessment. Physiologically based pharmacokinetic (PBPK(2)) modeling is the most potent in silico tool used for extrapolation of pharmacokinetic parameters to animal or human models from results obtained in vitro...
July 27, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28810741/photochemical-synthesis-of-3-azabicyclo-3-2-0-heptanes-advanced-building-blocks-for-drug-discovery
#8
Aleksandr V Denisenko, Tetiana Druzhenko, Yevhen Skalenko, Maryna Samoilenko, Oleksandr O Grygorenko, Sergey Zozulya, Pavel K Mykhailiuk
We have developed a rapid two-step synthesis of substituted 3 azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals - benzaldehyde, allylamine and cinnamic acid, - via intramolectular [2+2] photochemical cyclization.
August 16, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28810126/combined-virtual-screening-and-substructure-search-for-discovery-of-novel-fabp4-inhibitors
#9
Haiyan Cai, Ting Wang, Zhuo Yang, Zhijian Xu, Guimin Wang, Heyao Wang, Weiliang Zhu, Kaixian Chen
Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 <10 μM, among which eleven compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 μM. Molecular docking and point mutation studies revealed that Gln95, Arg126 and Tyr128 play key roles for these compounds binding with FABP4...
August 15, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28810125/cheminformatic-analysis-of-anti-malarial-chemical-space-illuminates-therapeutic-mechanisms-and-offers-strategies-for-therapy-development
#10
Julia Nogueira Varela, María Fernanda Fernanda Lammoglia Cobo, Sandip V Pawar, Vikramaditya G Yadav
The clear and present danger of malaria, which has been amplified in recent years by climate change, and the progressive thinning of our drug arsenal over the past two decades raise uncomfortable questions about the current state and future of anti-malarial drug development. Besides suffering from many of the same technical challenges that affect drug development in other disease areas, the quest for new anti-malarial therapies is also hindered by the complex, dynamic life cycle of the malaria parasite, P. falciparum, in its mosquito and human hosts, and its role thereof in the elicitation of drug resistance...
August 15, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28809565/dipicolinic-acid-derivatives-as-inhibitors-of-new-delhi-metallo-%C3%AE-lactamase-1
#11
Allie Y Chen, Pei W Thomas, Alesha C Stewart, Alexander Bergstrom, Zishuo Cheng, Callie Miller, Christopher R Bethel, Steven H Marshall, Cy V Credille, Christopher L Riley, Richard C Page, Robert A Bonomo, Michael W Crowder, David L Tierney, Walter Fast, Seth M Cohen
The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase-(MBL) mediated resistance, specifically New Delhi-Metallo-β- lactamase-1 (NDM-1). Utilizing fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. Based on 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes...
August 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28808415/foxo-signaling-pathways-as-therapeutic-targets-in-cancer
#12
REVIEW
Mohd Farhan, Haitao Wang, Uma Gaur, Peter J Little, Jiangping Xu, Wenhua Zheng
Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28808272/a-combinatorial-approach-for-the-discovery-of-cytochrome-p450-2d6-inhibitors-from-nature
#13
Johannes Hochleitner, Muhammad Akram, Martina Ueberall, Rohan A Davis, Birgit Waltenberger, Hermann Stuppner, Sonja Sturm, Florian Ueberall, Johanna M Gostner, Daniela Schuster
The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28806076/structure-affinity-relationships-and-structure-kinetics-relationships-of-pyrido-2-1-f-purine-2-4-dione-derivatives-as-human-adenosine-a3-receptor-antagonists
#14
Lizi Xia, Wessel A C Burger, Jacobus P D van Veldhoven, Boaz J Kuiper, Tirsa T van Duijl, Eelke B Lenselink, Ellen Paasman, Laura H Heitman, Adriaan P IJzerman
We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A3 receptor (hA3R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hA3R antagonists with very short residence time at the receptor (RT of 2.2 min for 5) and much longer RTs (e.g. 376 min for 27, or 391 min for 31). Two representative antagonists (5 and 27) were tested in [(35)S]GTPγS binding assays, and their RTs appeared correlated to their (in)surmountable antagonism...
August 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28805813/analysis-of-genome-wide-association-data-highlights-candidates-for-drug-repositioning-in-psychiatry
#15
Hon-Cheong So, Carlos Kwan-Long Chau, Wan-To Chiu, Kin-Sang Ho, Cho-Pong Lo, Stephanie Ho-Yue Yim, Pak-Chung Sham
Knowledge of psychiatric disease genetics has advanced rapidly during the past decade with the advent of genome-wide association studies (GWAS). However, less progress has been made in harnessing these data to reveal new therapies. Here we propose a framework for drug repositioning by comparing transcriptomes imputed from GWAS data with drug-induced gene expression profiles from the Connectivity Map database and apply this approach to seven psychiatric disorders. We found a number of repositioning candidates, many supported by preclinical or clinical evidence...
August 14, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28805182/human-induced-pluripotent-stem-cells-as-a-research-tool-in-alzheimer-s-disease
#16
J P Robbins, J Price
Human-induced pluripotent stem cells (iPSCs) offer a novel, timely approach for investigating the aetiology of neuropsychiatric disorders. Although we are starting to gain more insight into the specific mechanisms that cause Alzheimer's disease and other forms of dementia, this has not resulted in therapies to slow the pathological processes. Animal models have been paramount in studying the neurobiological processes underlying psychiatric disorders. Nonetheless, these human conditions cannot be entirely recapitulated in rodents...
August 14, 2017: Psychological Medicine
https://www.readbyqxmd.com/read/28805165/repurposing-as-a-strategy-for-the-discovery-of-new-anti-leishmanials-the-state-of-the-art
#17
Rebecca L Charlton, Bartira Rossi-Bergmann, Paul W Denny, Patrick G Steel
Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio-economic hardship, best measured in 2·4 million disability adjusted life years, with greatest impact on the poorest communities, which means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected tropical disease...
August 14, 2017: Parasitology
https://www.readbyqxmd.com/read/28805059/probing-membrane-receptor-ligand-specificity-with-surface-and-tip-enhanced-raman-scattering
#18
Lifu Xiao, Karen A Bailey, Hao Wang, Zachary D Schultz
The specific interaction between a ligand and a protein is a key component in minimizing off-target effects in drug discovery. Investigating these interactions with membrane protein receptors can be quite challenging. In this report, we show how spectral variance observed in surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) can be correlated with ligand specificity in affinity-based assays. Variations in the enhanced Raman spectra of three peptide ligands (i.e. cyclic-RGDFC, cyclic-isoDGRFC, and CisoDGRC), which have different binding affinity to αvβ3 integrin, are reported from isolated proteins and from receptors in intact cancer cell membranes...
August 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28803677/indole-fused-azepines-and-analogues-as-anticancer-lead-molecules-privileged-findings-and-future-directions
#19
REVIEW
Ashok K Singh, Vinit Raj, Sudipta Saha
The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major intention of cancer drug discovery now a days. For the time being, indole-fused azepines emerged as a simple class of compounds prolifically designed with strong pharmacological significances in particular of cancer protecting ability. In the recent years from the efforts of our research group, indole-fused heteroazepines, a simple structural class achieved by fusion of indole with oxygen, sulphur and nitrogen containing heteroazepine rings, have known for its superior outcomes in cancer treatment...
August 4, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28803044/new-racemic-annulated-pyrazolo-1-2-b-phthalazines-as-tacrine-like-ache-inhibitors-with-potential-use-in-alzheimer-s-disease
#20
Leili Jalili-Baleh, Hamid Nadri, Alireza Moradi, Syed Nasir Abbas Bukhari, Mojtaba Shakibaie, Mandana Jafari, Mostafa Golshani, Farshad Homayouni Moghadam, Loghman Firoozpour, Ali Asadipour, Saeed Emami, Mehdi Khoobi, Alireza Foroumadi
A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells...
July 31, 2017: European Journal of Medicinal Chemistry
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