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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 ...
July 17, 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...
April 18, 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 due to 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 non-muscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score > 0...
June 14, 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...
June 7, 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
Farah Al Madfai, Syed Tabish R Zaidi, Long Chiau Ming, Troy Wanandy, Rahul P Patel
PURPOSE: The stability of milrinone in continuous ambulatory delivery devices (CADDs) stored at 4, 25, and 35 °C was evaluated. METHOD: Six CADDs (3 devices containing milrinone plus 0.9% sodium chloride injection and 3 devices containing milrinone plus 5% dextrose injection) were prepared. Devices were kept at 4 °C for 168 hours, followed by 24 hours at 25 °C and an additional 24 hours at 35 °C. Samples ( n = 3) were withdrawn aseptically at 0, 24, 48, 72, 96, 120, 144, and 168 hours from the CADDs stored at 4 °C and at 0, 6, and 24 hours from the CADDs stored at 25 and 35 °C...
May 1, 2018: American Journal of Health-system Pharmacy: AJHP
Kirtee Baheti, Mayura Ajay Kale
BACKGROUND: Since last two decades, there has been more focus on the development strategies related to Anti-Alzheimer's drug research. This may be attributed to the fact that most of the Alzheimer's cases are still mostly unknown except for a few cases, where genetic differences have been identified. With the progress of the disease, the symptoms involve intellectual deterioration, memory impairment, abnormal personality and behavioural patterns, confusion, aggression, mood swings, irritability Current therapies available for this disease give only symptomatic relief and do not focus on manipulations of biololecular processes...
April 17, 2018: Current Drug Discovery Technologies
Amit Lather, Sunil Sharma, Anurag Khatkar
BACKGROUND: Infections caused by microorganisms are the major cause of death today. The tremendous and improper use of antimicrobial agents leads to antimicrobial resistance. AIM AND OBJECTIVE: Various currently available antimicrobial drugs are inadequate to control the infections and lead to various adverse drug reactions. Efforts based on computer-aided drug design (CADD) can excavate a large number of databases to generate new, potent hits and minimize the requirement of time as well as money for the discovery of newer antimicrobials...
2018: Combinatorial Chemistry & High Throughput Screening
Bing Yang, Xiaobo Li, Lu He, Yu Zhu
Despite the development of temozolomide (TMZ), a novel type of glioma therapeutic drug, malignant glioma remains to cause severe damage to human health. The present study aimed to utilize the molecular biological differences between tumor and normal cells to design TMZ derivatives with improved selectivity and targeting using computer-aided drug design (CADD). Taking alkylglycerone phosphate synthase (AGPS) as a target, a 3D structure-activity relationship model was built using CADD technology; molecular docking of isothiocyanate (ITC) and TMZ compounds was conducted; ITC-TMZ derivatives were designed; and predictions on the absorption, distribution, metabolism and excretion (ADME) processes and toxicity of the ITC-TMZ derivatives were established in order to obtain improved understanding of the structure-activity relationship of the candidate compounds...
March 2018: Biomedical Reports
Ok Tae Kim, Yurry Um, Mei Lan Jin, Jang Uk Kim, Daniela Hegebarth, Lucas Busta, Radu C Racovita, Reinhard Jetter
Centella asiatica is widely used as a medicinal plant due to accumulation of the ursane-type triterpene saponins asiaticoside and madecassoside. The molecular structure of both compounds suggests that they are biosynthesized from α-amyrin via three hydroxylations, and the respective Cyt P450-dependent monooxygenases (P450 enzymes) oxidizing the C-28 and C-2α positions have been reported. However, a third enzyme hydroxylating C-23 remained elusive. We previously identified 40,064 unique sequences in the transcriptome of C...
June 1, 2018: Plant & Cell Physiology
Trevor J Pemberton, Zachary A Szpiech
Genomic regions of autozygosity (ROAs) represent segments of individual genomes that are homozygous for haplotypes inherited identical-by-descent (IBD) from a common ancestor. ROAs are nonuniformly distributed across the genome, and increased ROA levels are a reported risk factor for numerous complex diseases. Previously, we hypothesized that long ROAs are enriched for deleterious homozygotes as a result of young haplotypes with recent deleterious mutations-relatively untouched by purifying selection-being paired IBD as a consequence of recent parental relatedness, a pattern supported by ROA and whole-exome sequence data on 27 individuals...
April 5, 2018: American Journal of Human Genetics
Shaoyi Cai, Gengzheng Zhu, Xiaohong Cen, Jingjie Bi, Jingru Zhang, Xiaoshan Tang, Kun Chen, Kui Cheng
Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N-benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50 =18.21 ± 0.87 μM)...
May 1, 2018: Bioorganic & Medicinal Chemistry
F Al Madfai, B Valah, S T R Zaidi, T Wanandy, L C Ming, G M Peterson, R P Patel
WHAT IS KNOWN AND OBJECTIVE: Continuous infusion of dobutamine plays an important role in the management of patients with end-stage heart failure. Home infusion of dobutamine using a continuous ambulatory delivery device (CADD) facilitates the management of patients in their home, avoiding complications associated with long-term hospitalization. However, the stability of dobutamine in CADD is currently unknown. Therefore, this study investigated the physicochemical stability of dobutamine in CADDs at three different temperatures over various time points...
August 2018: Journal of Clinical Pharmacy and Therapeutics
Md Wasimul Haque, Shakti Prasad Pattanayak
Background: Breast cancer (BC), because of its invasive characteristics, is one of the most common and deadliest cancers among the female population around the world. Research has demonstrated that AhR signaling also plays a vital role in BC initiation and development as well. Therefore, blocking this pathway to natural interferences paves a new channel for the prevention of BC. Several natural compounds such as flavonoids possess the anticancer activities against different cancers. Objective: The present study has been designed to estimate the chemotherapeutic potential of taxifolin (TAX) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in Sprague-Dawley rats...
January 2018: Pharmacognosy Magazine
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