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Morgan Brittany Johnson, Justin R Halman, Emily Satterwhite, Alexey V Zakharov, My N Bui, Kheiria Benkato, Victoria Goldsworthy, Taejin Kim, Enping Hong, Marina A Dobrovolskaia, Emil F Khisamutdinov, Ian Marriott, Kirill A Afonin
In the past few years, the study of therapeutic RNA nanotechnology has expanded tremendously to encompass a large group of interdisciplinary sciences. It is now evident that rationally designed programmable RNA nanostructures offer unique advantages in addressing contemporary therapeutic challenges such as distinguishing target cell types and ameliorating disease. However, to maximize the therapeutic benefit of these nanostructures, it is essential to understand the immunostimulatory aptitude of such tools and identify potential complications...
September 18, 2017: Small
Xiaolei Wang, Zhenhua Chu, Jiawen Yang, Yu Li
A three-dimensional quantitative structure activity relationship (3D-QSAR) model is built by using a comparative molecular similarity indices analysis (CoMSIA) technique with an experimentally determined logarithm of bioconcentration factors (logBCFs) for 36 phenols in fish. Meanwhile, with the pentachlorophenol (PCP) molecule as target molecules, contributions of the molecular fields indicate that the electrostatic fields are the main influences on the bioconcentration of the PCP molecule. Based on the analytical results of CoMSIA contour map of PCP and PCP molecular docking with SOD protease (PDB ID: 4A7T), the R6 substituent positions of PCP were modified to give seven new modified PCP molecules with low bioconcentration in this paper...
September 18, 2017: Environmental Science and Pollution Research International
Shengrong Li, Jilin Fan, Chengkang Peng, Yiqun Chang, Lianxia Guo, Jinsong Hou, Miaoqi Huang, Biyuan Wu, Junxia Zheng, Longxin Lin, Gaokeng Xiao, Weimin Chen, Guochao Liao, Jialiang Guo, Pinghua Sun
Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q (2) = 0...
September 14, 2017: Scientific Reports
Yingnan Han, Mei Ma, Na Li, Rui Hou, Chao Huang, Yoshimitsu Oda, Zijian Wang
Investigations have focused on the removal and transformation of pharmaceuticals during drinking water and wastewater treatment. In the present study, we investigated for the first time the changes of the cytotoxicity and genotoxicity based on different modes of action (MoAs) during chlorination, chloramination and ozonation processes of the anti-epileptic drug carbamazepine (CBZ). The results illustrated that ozonation enhanced the cytotoxicity and the chromosome damage effects on CHO-K1 cells detected by cytokinesis-block micronucleus (CBMN) assay based on high-content screening technique, though ozonation showed the highest removal efficiency for CBZ...
September 1, 2017: Journal of Hazardous Materials
Nirzari Gupta, Vivek K Vyas, Bhumika D Patel, Manjunath Ghate
Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q (2)) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively...
September 11, 2017: Interdisciplinary Sciences, Computational Life Sciences
Wen Zhang, Kai-Xiong Qiu, Fang Yu, Xiao-Guang Xie, Shu-Qun Zhang, Ya-Juan Chen, Hui-Ding Xie
B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔGbind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines...
August 31, 2017: Computational Biology and Chemistry
Kurumurthy Kammari, Kiran Devaraya, Akhila Bommakanti, Anand K Kondapi
AIM: A structural study of a series of pyridine dicoumarol derivatives with potential activity against a novel Topoisomerase IIβ kinase which was identified in the HIV-1 viral lysate, compounds were designed and synthesized based on a 3D-QSAR study. MATERIALS & METHODS: Based on QSAR model we have designed and synthesized a series of pyridine dicoumarol derivatives and characterized by spectral studies, all the molecules are biologically evaluated by kinase assay, cytotoxicity assay, ELISA and PCR method...
September 11, 2017: Future Medicinal Chemistry
Lu Zhang, Jianjun Tan, Dan Han, Hao Zhu
Machine intelligence, which is normally presented as artificial intelligence, refers to the intelligence exhibited by computers. In the history of rational drug discovery, various machine intelligence approaches have been applied to guide traditional experiments, which are expensive and time-consuming. Over the past several decades, machine-learning tools, such as quantitative structure-activity relationship (QSAR) modeling, were developed that can identify potential biological active molecules from millions of candidate compounds quickly and cheaply...
September 4, 2017: Drug Discovery Today
Gang Chen, Di Zhou, Xue-Zheng Li, Zhe Jiang, Chengyu Tan, Xiu-Yan Wei, Junhong Ling, Jing Jing, Fen Liu, Ning Li
This study was to study the antitumor effect of lonchocarpin (34) from traditional herbal medicine Pongamia pinnata (L.) Pierre and to reveal the underlying mechanism. The cytotoxic activities of lonchocarpin were evaluated in 10 lung cancer cell lines and it exhibited 97.5% activity at a dose of 100 μM in the H292 cell line. A field-based quantitative structure-activity relationship (3D-QSAR) study of 37 flavonoids from P. pinnata was also performed, and the results obtained showed that the hydrophobic interaction could be the crucial factor for the antitumor activity of lonchocarpin...
September 6, 2017: Scientific Reports
Giovanna Cardoso Gajo, Daniela Rodrigues Silva, Stephen J Barigye, Elaine Fontes Ferreira da Cunha
Despite recent advances in Computer Aided Drug Discovery and High Throughput Screening, the attrition rates of drug candidates continue to be high, underscoring the inherent complexity of the drug discovery paradigm. Indeed, a compromise between several objectives is often required to obtain successful clinical drugs. The present manuscript details a multi-objective workflow that integrates the 4D-QSAR and molecular docking methods in the simultaneous modeling of the Rho Kinase inhibitory activity and acute toxicity of Benzamide derivatives...
September 6, 2017: Molecular Informatics
Naresh Kumar Katari, Tejeswara Rao Allaka, Venkataramireddy Veeramreddy, Jaya Shree Anireddy
BACKGROUND: Fluoroquinolones have been the centre of considerable scientific and clinical interest due to their broad spectrum pharmacological activities. Pefloxacin is an analogue of norfloxacin, which is a 3rd generation of fluoroquinolone [5] antibiotic similar to ciprofloxacin. Pefloxacin is used to treat a variety of bacterial infections like respiratory tract, ear, nose and throat (ENT) infections, skin infections, urinary tract infections. Hydrazone as a pharmacophore unit that attract the medicinal chemists because of structure activity relationship (SAR) studies of fluoroquinolones especially the functionality at C-3 position...
August 29, 2017: Current Drug Discovery Technologies
Yuting Xu, Junshui Ma, Andy Liaw, Robert P Sheridan, Vladimir Svetnik
Deep neural networks (DNNs) are complex computational models that have found great success in many artificial intelligence applications, such as computer vision and natural language processing. In the past four years, DNNs also generated promising results for quantitative structure-activity relationship (QSAR) tasks. Previous work showed that DNNs can routinely make better predictions than traditional methods, such as random forests, on a diverse collection of QSAR datasets. It was also found that multi-task DNN models - those trained on and predicting multiple QSAR properties simultaneously - outperform DNNs trained separately on the individual datasets in many but not all tasks...
September 5, 2017: Journal of Chemical Information and Modeling
Maja Molnar, Mario Komar, Harshad Brahmbhatt, Jurislav Babić, Stela Jokić, Vesna Rastija
Deep eutectic solvents, as green and environmentally friendly media, were utilized in the synthesis of novel coumarinyl Schiff bases. Novel derivatives were synthesized from 2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetohydrazide and corresponding aldehyde in choline chloride:malonic acid (1:1) based deep eutectic solvent. In these reactions, deep eutectic solvent acted as a solvent and catalyst as well. Novel Schiff bases were synthesized in high yields (65-75%) with no need for further purification, and their structures were confirmed by mass spectra, ¹H and (13)C NMR...
September 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Abdalla R Mohamed, Hanan H Georgey, Riham F George, Wafaa I El-Eraky, Dalia O Saleh, Nagwa M Abdel Gawad
AIM: The discovery of new bronchodilators with higher efficacy than theophylline is an important issue for asthmatic patients. MATERIALS & METHODS: Theophylline 2, 8-bromotheophylline 4 and theobromine 6 were reacted with different 2/3-chloro-N-phenylacetamides 1a-d or their propanamide analogs 1e-g to obtain 3a-g, 5a-g and 7a-g, respectively. The target compounds were screened for their in vitro bronchodilator activity using isolated guinea pig tracheal rings precontracted with histamine and compared with their precursors...
September 5, 2017: Future Medicinal Chemistry
Alicia Paini, Jeremy A Leonard, Tomas Kliment, Yu-Mei Tan, Andrew Worth
Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration...
September 1, 2017: Regulatory Toxicology and Pharmacology: RTP
Giuseppe Floresta, Antonio Rescifina, Agostino Marrazzo, Maria Dichiara, Venerando Pistarà, Valeria Pittalà, Orazio Prezzavento, Emanuele Amata
A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the σ2 receptor affinity has been constructed with the aim of providing a useful tool for the identification, design, and optimization of novel σ2 receptor ligands. The model has been built using a set of 500 selective σ2 receptor ligands recovered from the sigma-2 receptor selective ligand database (S2RSLDB) and developed with the software Forge. The present model showed high statistical quality as confirmed by its robust predictive potential and satisfactory descriptive capability...
August 25, 2017: European Journal of Medicinal Chemistry
Nilanjan Adhikari, Sk Abdul Amin, Balaram Ghosh, Tarun Jha
Human meprin (EC is a member of the metzincin superfamily. It correlates with matrix metalloproteinases and ADAMs (a disintegrin and metalloproteinase domain). Overexpression of meprin β is implicated in fibrosis, inflammatory diseases, and cancers. However, selective meprin β inhibition is crucial to reduce cancer metastasis and adverse effects in inflammation. It also plays critical roles in modulating several interleukins and growth factors. Moreover, meprin β cleaves amyloid precursor protein (APP), thought to be involved in the progression of Alzheimer's disease...
September 1, 2017: Journal of Biomolecular Structure & Dynamics
Xuehua Zheng, Siyuan Zhou, Chen Zhang, Deyan Wu, Hai-Bin Luo, Yinuo Wu
Recently, a series of xanthone analogues has been identified as α-glucosidase inhibitors. To provide deeper insight into the three-dimensional (3D) structural requirements for the activities of these molecules, CoMFA and CoMSIA approaches were employed on 54 xanthones to construct 3D-QSAR models. Their bioactive conformations were first investigated by docking studies and optimized by subsequent molecular dynamics (MD) simulations using the homology modeled structure of the target protein. Based on the docking/MD-determined conformers, 3D-QSAR studies generated several significant models in terms of 47 molecules as the training set...
August 31, 2017: Journal of Molecular Modeling
Pakhuri Mehta, Shubham Srivastava, Bhanwar Singh Choudhary, Manish Sharma, Ruchi Malik
Multidrug resistance along with side-effects of available anti-epileptic drugs and unavailability of potent and effective agents in submicromolar quantities presents the biggest therapeutic challenges in anti-epileptic drug discovery. The molecular modeling techniques allow us to identify agents with novel structures to match the continuous urge for its discovery. KCNQ2 channel represents one of the validated targets for its therapy. The present study involves identification of newer anti-epileptic agents by means of a computer-aided drug design adaptive protocol involving both structure-based virtual screening of Asinex library using homology model of KCNQ2 and 3D-QSAR based virtual screening with docking analysis, followed by dG bind and ligand efficiency calculations with ADMET studies, of which 20 hits qualified all the criterions...
August 31, 2017: Journal of Receptor and Signal Transduction Research
Karen Reyes-Melo, Abraham García, Antonio Romo-Mancillas, Elvira Garza-González, Verónica M Rivas-Galindo, Luis D Miranda, Javier Vargas-Villarreal, Juan Manuel J Favela-Hernández, María Del Rayo Camacho-Corona
Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium...
July 29, 2017: Bioorganic & Medicinal Chemistry
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