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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
Chiara Luise, Dina Robaa
Computer-based approaches represent a powerful tool which helps to identify and optimize lead structures in the process of drug discovery. Computer-aided drug design techniques (CADD) encompass a large variety of methods which are subdivided into structure-based (SBDD) and ligand-based drug design (LBDD) methods. Several approaches have been successfully used over the last three decades in different fields. Indeed also in the field of epigenetics, virtual screening (VS) studies and structure-based approaches have been applied to identify novel chemical modulators of epigenetic targets as well as to predict the binding mode of active ligands and to study the protein dynamics...
2018: Methods in Molecular Biology
Liyu Qian, Yu Zhu
Background: Glioma and breast cancer are severe malignant cancerous tumors that highlight the importance of developing new anti-cancer drugs. The aim of this study was to explore the effects of a novel nitrogenous heterocyclic compound on glioma and breast cancer cells and to determine its mechanism of action. Methods: We designed and synthesized a novel nitrogenous heterocyclic compound, 3-(4-amino-1H-benzo[d]imidazole-2-carboxamido)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5] tetrazine-8-carboxamide, based on alkylglycerone phosphate synthase (AGPS) using computer-aided drug design (CADD), and we measured its effect on the proliferation, invasion, cell cycle and apoptosis of U251 glioma and MCF-7 breast cancer cells...
2018: Drug Design, Development and Therapy
Huimin Cheng, Brian M Linhares, Wenbo Yu, Mariano G Cardenas, Yong Ai, Wenjuan Jiang, Alyssa Winkler, Sandra Cohen, Ari Melnick, Alexander MacKerell, Tomasz Cierpicki, Fengtian Xue
Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB ) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6BTB has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to BCL6BTB . From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X-ray crystallography has yielded an inhibitor, 15f, that demonstrated over 100-fold improved potency for BCL6BTB ...
September 13, 2018: Journal of Medicinal Chemistry
Kévin Vervier, Jacob J Michaelson
Motivation: Model-based estimates of general deleteriousness, like CADD, DANN or PolyPhen, have become indispensable tools in the interpretation of genetic variants. However, these approaches say little about the tissues in which the effects of deleterious variants will be most meaningful. Tissue-specific annotations have been recently inferred for dozens of tissues/cell types from large collections of cross-tissue epigenomic data, and have demonstrated sensitivity in predicting affected tissues in complex traits...
September 15, 2018: Bioinformatics
Elena I Fomchenko, Daniel Duran, Sheng Chih Jin, Weilai Dong, E Zeynep Erson-Omay, Prince Antwi, August Allocco, Jonathan R Gaillard, Anita Huttner, Murat Gunel, Michael L DiLuna, Kristopher T Kahle
Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0...
August 2018: Cold Spring Harbor Molecular Case Studies
Muhammad Shakeel, Muhammad Irfan, Ishtiaq Ahmad Khan
Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system...
October 5, 2018: Gene
Marina V Shulskaya, Anelya Kh Alieva, Ivan N Vlasov, Vladimir V Zyrin, Ekaterina Yu Fedotova, Natalia Yu Abramycheva, Tatiana S Usenko, Andrei F Yakimovsky, Anton K Emelyanov, Sofya N Pchelina, Sergei N Illarioshkin, Petr A Slominsky, Maria I Shadrina
Background : Parkinson's disease (PD) is a complex disease with its monogenic forms accounting for less than 10% of all cases. Whole-exome sequencing (WES) technology has been used successfully to find mutations in large families. However, because of the late onset of the disease, only small families and unrelated patients are usually available. WES conducted in such cases yields in a large number of candidate variants. There are currently a number of imperfect software tools that allow the pathogenicity of variants to be evaluated...
2018: Frontiers in Aging Neuroscience
Karen S Raraigh, Sangwoo T Han, Emily Davis, Taylor A Evans, Matthew J Pellicore, Allison F McCague, Anya T Joynt, Zhongzhou Lu, Melis Atalar, Neeraj Sharma, Molly B Sheridan, Patrick R Sosnay, Garry R Cutting
Missense DNA variants have variable effects upon protein function. Consequently, interpreting their pathogenicity is challenging, especially when they are associated with disease variability. To determine the degree to which functional assays inform interpretation, we analyzed 48 CFTR missense variants associated with variable expressivity of cystic fibrosis (CF). We assessed function in a native isogenic context by evaluating CFTR mutants that were stably expressed in the genome of a human airway cell line devoid of endogenous CFTR expression...
June 7, 2018: American Journal of Human Genetics
Lyse Ruaud, Gillian I Rice, Christelle Cabrol, Juliette Piard, Mathieu Rodero, Lien van Eyk, Elise Boucher-Brischoux, Alain Maertens de Noordhout, Ricardo Maré, Emmanuel Scalais, Fernand Pauly, François-Guillaume Debray, William Dobyns, Carolina Uggenti, Ji Woo Park, Sun Hur, John H Livingston, Yanick J Crow, Lionel Van Maldergem
We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives...
August 2018: Human Mutation
Fahad A Al-Abbasi, Kaleemuddin Mohammed, Saida Sadath, Babajan Banaganapalli, Khalidah Nasser, Noor A Shaik
The deleterious amino acid substitution mutations in IL-10 receptor alpha gene are most frequently reported in several autoimmune diseases including early onset-inflammatory bowel disease (IBD). Despite the important role of IL-10 RA in maintaining immune homeostasis, the specific structural and functional implications of these mutations on protein phenotype, stability, ligand binding and post translational characteristics is not well explored. Therefore, this study performed the multidimensional computational analysis of IL10RA missense variations causative to pediatric or early onset inflammatory bowel disease (<5 years of age)...
2018: Frontiers in Genetics
Eliot Boulanger, Lei Huang, Chetan Rupakheti, Alexander D MacKerell, Benoît Roux
Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein-ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule...
June 12, 2018: Journal of Chemical Theory and Computation
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