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Baiqing Li, Chunfeng Ma, Xiaoyong Zhao, Zhigang Hu, Tengfei Du, Xuanming Xu, Zhonghua Wang, Jianping Lin
Traditional Chinese Medicine (TCM) has a long history of widespread clinical applications, especially in East Asia, and is becoming frequently used in Western countries. However, owing to extreme complicacy in both chemical ingredients and mechanism of action, a deep understanding of TCM is still difficult. To accelerate the modernization and popularization of TCM, a single comprehensive database is required, containing a wealth of TCM-related information and equipped with complete analytical tools. Here we present YaTCM (Yet another Traditional Chinese Medicine database), a free web-based toolkit, which provides comprehensive TCM information and is furnished with analysis tools...
2018: Computational and Structural Biotechnology Journal
Lies Van Horebeek, Kelly Hilven, Klara Mallants, Annemarie Van Nieuwenhuijze, Tiina Kelkka, Paula Savola, Satu Mustjoki, Susan M Schlenner, Adrian Liston, Bénédicte Dubois, An Goris
The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0...
December 12, 2018: Human Molecular Genetics
Peng Zhang, Benedetta Bigio, Franck Rapaport, Shen-Ying Zhang, Jean-Laurent Casanova, Laurent Abel, Bertrand Boisson, Yuval Itan
Summary: Next-generation sequencing (NGS) generates large amounts of genomic data and reveals about 20 000 genetic coding variants per individual studied. Several mutation damage prediction scores are available to prioritize variants, but there is currently no application to help investigators to determine the relevance of the candidate genes and variants quickly and visually from population genetics data and deleteriousness scores. Here, we present PopViz, a user-friendly, rapid, interactive, mobile-compatible webserver providing a gene-centric visualization of the variants of any human gene, with (i) population-specific minor allele frequencies from the gnomAD population genetic database; (ii) mutation damage prediction scores from CADD, EIGEN and LINSIGHT and (iii) amino-acid positions and protein domains...
December 15, 2018: Bioinformatics
RamaKrishna Munnaluri, Saikiran Reddy Peddi, Sree Kanth Sivan, Vijjulatha Manga
The fight against tuberculosis (TB) is a time immemorial one and the emergence of new drug resistant strains of Mycobacterium tuberculosis keeps throwing new challenges to the scientific community immersed in finding mechanisms to control this dreaded disease. Computer aided drug designing (CADD) is one of the several approaches that can assist in identifying the potent actives against Mycobacterium. In this work, a series of 109 known Mycobacterial membrane proteins large 3 (MmpL3) inhibitors were pooled and atom based 3D QSAR analysis was performed to understand the structural features essential for inhibitory activity against the MmpL3, known to be a key player in transporting substances critical for cell wall integrity of Mycobacterium...
November 19, 2018: Computational Biology and Chemistry
Vinicius Gonçalves Maltarollo, Thales Kronenberger, Gabriel Zarzana Espinoza, Patricia Rufino Oliveira, Kathia Maria Honorio
Novel drug discovery remains an enormous challenge, with various computer-aided drug design (CADD) approaches having been widely employed for this purpose. CADD, specifically the commonly used support vector machines (SVMs), can employ machine learning techniques. SVMs and their variations offer numerous drug discovery applications, which range from the classification of substances (as active or inactive) to the construction of regression models and the ranking/virtual screening of databased compounds. Areas covered: Herein, the authors consider some of the applications of SVMs in medicinal chemistry, illustrating their main advantages and disadvantages, as well as trends in their utilization, via the available published literature...
November 29, 2018: Expert Opinion on Drug Discovery
Shang-Tao Chien, Ajay Kumar, Shifa Pandey, Chung-Kun Yen, Shao-Yu Wang, Zhi-Hong Wen, Aman Chandra Kaushik, Yow-Ling Shiue, Cheng-Tang Pan
BACKGROUND: Cancer is one of the most debilitating diseases in the world. Even though advances in molecular and cellular biology have contributed to the decline of mortality associated with cancer, the procedure of drug discovery and development of cancer is time-consuming and expensive. However, with computer-aided drug discovery (CADD) techniques, pharmaceutical firms can save production costs and reduce the time of introducing effective anticancer drugs to the market. CADD strategies like structure-based, ligand-based, and combined structure-based and ligand-based approaches also have the advantage of identifying target sites and discovering active compounds with high affinity for the target sites...
November 11, 2018: Current Pharmaceutical Design
Aoxiang Tao, Yuying Huang, Yasuhiro Shinohara, Matthew L Caylor, Srinath Pashikanti, Dong Xu
As abundant and user-friendly as computer-aided drug design (CADD) software may seem, there is still a large underserved population of biomedical researchers around the world, particularly those with no computational training and limited research funding. To address this important need and help scientists overcome barriers that impede them from leveraging CADD in their drug discovery work, we have developed ezCADD, a web-based CADD modeling environment that manifests four simple design concepts: easy, quick, user-friendly, and 2D/3D visualization-enabled...
November 16, 2018: Journal of Chemical Information and Modeling
Regie Lyn P Santos-Cortez, Charlotte M Chiong, Daniel N Frank, Allen F Ryan, Arnaud P J Giese, Tori Bootpetch Roberts, Kathleen A Daly, Matthew J Steritz, Wasyl Szeremeta, Melquiadesa Pedro, Harold Pine, Talitha Karisse L Yarza, Melissa A Scholes, Erasmo Gonzalo D V Llanes, Saira Yousaf, Norman Friedman, Ma Leah C Tantoco, Todd M Wine, Patrick John Labra, Jeanne Benoit, Amanda G Ruiz, Rhodieleen Anne R de la Cruz, Christopher Greenlee, Ayesha Yousaf, Jonathan Cardwell, Rachelle Marie A Nonato, Dylan Ray, Kimberly Mae C Ong, Edward So, Charles E Robertson, Jordyn Dinwiddie, Sheryl Mae Lagrana-Villagracia, Samuel P Gubbels, Rehan S Shaikh, Stephen P Cass, Elisabet Einarsdottir, Nanette R Lee, David A Schwartz, Teresa Luisa I Gloria-Cruz, Michael J Bamshad, Ivana V Yang, Juha Kere, Generoso T Abes, Jeremy D Prager, Saima Riazuddin, Abner L Chan, Patricia J Yoon, Deborah A Nickerson, Eva Maria Cutiongco-de la Paz, Sven-Olrik Streubel, Maria Rina T Reyes-Quintos, Herman A Jenkins, Petri Mattila, Kenny H Chan, Karen L Mohlke, Suzanne M Leal, Lena Hafrén, Tasnee Chonmaitree, Michele M Sale, Zubair M Ahmed
Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗ ) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p...
November 1, 2018: American Journal of Human Genetics
Philipp Rentzsch, Daniela Witten, Gregory M Cooper, Jay Shendure, Martin Kircher
Combined Annotation-Dependent Depletion (CADD) is a widely used measure of variant deleteriousness that can effectively prioritize causal variants in genetic analyses, particularly highly penetrant contributors to severe Mendelian disorders. CADD is an integrative annotation built from more than 60 genomic features, and can score human single nucleotide variants and short insertion and deletions anywhere in the reference assembly. CADD uses a machine learning model trained on a binary distinction between simulated de novo variants and variants that have arisen and become fixed in human populations since the split between humans and chimpanzees; the former are free of selective pressure and may thus include both neutral and deleterious alleles, while the latter are overwhelmingly neutral (or, at most, weakly deleterious) by virtue of having survived millions of years of purifying selection...
October 29, 2018: Nucleic Acids Research
Yu Wei, Jinlong Li, Baiqing Li, Chunfeng Ma, Xuanming Xu, Xu Wang, Aqin Liu, Tengfei Du, Zhonghua Wang, Zhangyong Hong, Jianping Lin
Glaucoma is a group of neurodegenerative diseases that can cause irreversible blindness. The current medications, which mainly reduce intraocular pressure to slow the progression of disease, may have local and systemic side effects. Recently, medications with possible neuroprotective effects have attracted much attention. To assist in the identification of new glaucoma drugs, we created a glaucomatous chemogenomics database (GCDB; in which various glaucoma-related chemogenomics data records are assembled, including 275 genes, 105 proteins, 83 approved or clinical trial drugs, 90 206 chemicals associated with 213 093 records of reported bioactivities from 22 324 corresponding bioassays and 5630 references...
January 1, 2018: Database: the Journal of Biological Databases and Curation
Zachary D Wallen, Honglei Chen, Erin M Hill-Burns, Stewart A Factor, Cyrus P Zabetian, Haydeh Payami
Objective: To identify modifiers of age at diagnosis of Parkinson disease (PD). Methods: Genome-wide association study (GWAS) included 1,950 individuals with PD from the NeuroGenetics Research Consortium (NGRC) study. Replication was conducted in the Parkinson's, Genes and Environment study, including 209 prevalent (PAGEP ) and 517 incident (PAGEI ) PD cases. Cox regression was used to test association with age at diagnosis. Individuals without neurologic disease were used to rule out confounding...
October 2018: Neurology. Genetics
Zhe Wang, Xuwen Wang, Youyong Li, Tailong Lei, Ercheng Wang, Dan Li, Yu Kang, Feng Zhu, Tingjun Hou
Summary: Protein-protein interactions (PPIs) have been regarded as an attractive emerging class of therapeutic targets for the development of new treatments. Computational approaches, especially molecular docking, have been extensively employed to predict the binding structures of PPI-inhibitors or discover novel small molecule PPI inhibitors. However, due to the relatively 'undruggable' features of PPI interfaces, accurate predictions of the binding structures for ligands towards PPI targets are quite challenging for most docking algorithms...
October 17, 2018: Bioinformatics
Christian Groß, Dick de Ridder, Marcel Reinders
BACKGROUND: Predicting the deleteriousness of observed genomic variants has taken a step forward with the introduction of the Combined Annotation Dependent Depletion (CADD) approach, which trains a classifier on the wealth of available human genomic information. This raises the question whether it can be done with less data for non-human species. Here, we investigate the prerequisites to construct a CADD-based model for a non-human species. RESULTS: Performance of the mouse model is competitive with that of the human CADD model and better than established methods like PhastCons conservation scores and SIFT...
October 12, 2018: BMC Bioinformatics
Tingting Zhang, Xiaoxue Zhao, Feifei Hou, Yanwei Sun, Jing Wu, Tengfei Ma, Xiangyu Zhang
OBJECTIVE: To investigate a novel gene mutation in a Chinese patient with non-syndromic hypodontia. SUBJECTS AND METHODS: Mutation analysis was carried out by whole exome sequencing. Bioinformatics tools were used for the biophysical predictions of the mutative protein. Luciferase reporter assay was performed to analyse the effects of mutation on protein function. PAX9 and BMP4 gene expression from mutant cells was detected by qRT-PCR. RESULTS: A novel heterozygous mutation (c...
September 26, 2018: Oral Diseases
Xibing He, Viet H Man, Beihong Ji, Xiang-Qun Xie, Junmei Wang
We participated in the Cathepsin S (CatS) sub-challenge of the Drug Design Data Resource (D3R) Grand Challenge 3 (GC3) in 2017 to blindly predict the binding poses of 24 CatS-bound ligands, the binding affinity ranking of 136 ligands, and the binding free energies of a subset of 33 ligands in Stage 1A and Stage 2. Our submitted predictions ranked relatively well compared to the submissions from other participants. Here we present our methodologies used in the challenge. For the binding pose prediction, we employed the Glide module in the Schrodinger Suite 2017 and AutoDock Vina...
September 14, 2018: Journal of Computer-aided Molecular Design
Rita Melo, Agostinho Lemos, António J Preto, Beatriz Bueschell, Pedro Matos-Filipe, Carlos Barreto, José G Almeida, Rúben D M Silva, João D G Correia, Irina Moreira
Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To-Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process...
September 4, 2018: Current Medicinal Chemistry
Faisel Abu-Duhier, Vivetha Pooranachandran, Andrew J G McDonagh, Andrew G Messenger, Johnathan Cooper-Knock, Youssef Bakri, Paul R Heath, Rachid Tazi-Ahnini
We report a family from Tabuk, Saudi Arabia, previously screened for Acrodermatitis Enteropathica (AE), in which two siblings presented with typical features of acral dermatitis and a pustular eruption but differing severity. Affected members of our family carry a rare genetic variant, p.Gly512Trp in the SLC39A4 gene which encodes a zinc transporter; disease is thought to result from zinc deficiency. Similar mutations have been reported previously; however, the variable severity within cases carrying the p...
2018: Dermatology Research and Practice
Jill F Ellenbarger, Inna V Krieger, Hsiao-Ling Huang, Silvia Gómez-Coca, Thomas R Ioerger, James C Sacchettini, Steven E Wheeler, Kim R Dunbar
Human infection by Mycobacterium tuberculosis (Mtb) continues to be a global epidemic. Computer-aided drug design (CADD) methods are used to accelerate traditional drug discovery efforts. One noncovalent interaction that is being increasingly identified in biological systems but is neglected in CADD is the anion-π interaction. The study reported herein supports the conclusion that anion-π interactions play a central role in directing the binding of phenyl-diketo acid (PDKA) inhibitors to malate synthase (GlcB), an enzyme required for Mycobacterium tuberculosis virulence...
September 12, 2018: Journal of Chemical Information and Modeling
Jing Zhang, Dan Wu, Yiqin Dai, Jianjiang Xu
Background: The genetic architecture underlying central cornea thickness (CCT) is far from understood. Most of the CCT-associated variants are located in the non-coding regions, raising the difficulty of following functional characterizations. Thus, integrative functional analyses on CCT-associated loci might benefit in overcoming these issues by prioritizing the hub genes that are located in the center of CCT genetic network. Methods: Integrative analyses including functional annotations, enrichment analysis, and protein-protein interaction analyses were performed on all reported CCT GWAS lead SNPs, together with their proxy variants...
2018: BioData Mining
Jiangkun Dai, Wenjia Dan, Na Li, Junru Wang
Thirty-two new 3,9-disubstituted eudistomin U derivatives were designed and synthesized based on computer-aided drug discovery (CADD). Sixteen 3,9-disubstituted eudistomin U derivatives (6a-6p) have exhibited potent antibacterial activity. Specially, the most active compound 6p displayed better activity than commercial drugs fosfomycin sodium, ciprofloxacin and propineb, with a peak minimum inhibitory concentration (MIC) of 1.5625 μmol/L. The antibacterial mechanism indicated that these compounds could exert bactericidal effect by damaging bacterial cell membrane and disrupting the function of DNA gyrase...
September 5, 2018: European Journal of Medicinal Chemistry
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