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HIV in silico

Wenchun Jiang, Xin Li, Tongyu Li, Hailian Wang, Wei Shi, Ping Qi, Chunyang Li, Jie Chen, Jinku Bao, Guodong Huang, Yi Wang
Computational drug repositioning by virtually screening existing drugs for additional therapeutic usage could efficiently accelerate anticancer drug discovery. Herein, a library of 1447 Food and Drug Administration (FDA)-approved small molecule drugs was screened in silico for inhibitors of extracellular signal-regulated kinase 2 (ERK2). Then, in vitro kinase assay demonstrated amprenavir, a HIV-1 protease inhibitor, as a potential kinase inhibitor of ERK2. The in vivo kinase assay indicated that amprenavir could inhibit ERK2-mediated phosphorylation of BimEL at Ser69...
March 2017: International Journal of Oncology
Maryam Ghafari, Mandana Behbahani, Hassan Mohabatkar
HIV-1 envelope (env) glycoprotein mediates an important role in entry of the virus into the susceptible target cells. As env glycoprotein of HIV-1 is highly variable in the different geographical regions, in the present study, different properties of this protein in Iran are compared with five nearby countries. The sequences of HIV-1 env glycoproteins of Iran, Afghanistan, Russia, Turkey, Pakistan and Saudi Arabia databases were collected from databases. Amino acid composition and physical and chemical properties of the proteins from these countries were studied using Protparam and COPid tools...
June 2016: Molecular Biology Research Communications
Maria Paximadis, Refilwe N Ngqobe, Richard E Chaisson, Neil A Martinson, Caroline T Tiemessen
An intronic single nucleotide polymorphism (SNP) in RICH2 (rs2072255; 255(i)), in complete linkage disequilibrium (LD) with an exonic SNP (rs2072254; 254(e)), has been identified in a genome wide association study to be associated with progression to AIDS in Caucasian individuals. RICH2 links tetherin to the cortical actin network and the RICH2/tetherin interaction has been shown to be important for the downstream activation of NF-κβ and the consequential promotion of proinflammatory responses. We investigated the role of these two SNPs in natural control of HIV-1 in black South Africans including healthy controls (HCs; N=102) and antiretroviral-naive HIV-1-infected controllers (HICs; N=52) and progressors (N=74)...
January 6, 2017: Infection, Genetics and Evolution
Daniel F Carr, Stephane Bourgeois, Mas Chaponda, Louise Y Takeshita, Andrew P Morris, Elena M Cornejo Castro, Ana Alfirevic, Andrew R Jones, Daniel J Rigden, Sam Haldenby, Saye Khoo, David G Lalloo, Robert S Heyderman, Collet Dandara, Elizabeth Kampira, Joep J van Oosterhout, Francis Ssali, Paula Munderi, Giuseppe Novelli, Paola Borgiani, Matthew R Nelson, Arthur Holden, Panos Deloukas, Munir Pirmohamed
BACKGROUND: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity. METHODS: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults...
January 6, 2017: Journal of Antimicrobial Chemotherapy
Abosede Oluwabukola Jaiyeola, K Anand, K Kasumbwe, M Ramesh, R M Gengan
The α-amino phosphonates exhibit a wide range of biological properties which create demand for simple and efficient synthetic routes of new molecules. In this study synthesis of a new series of derivatives of α-amino chromone phosphonates (ACPs) was reported using RhBT catalyst. The RhBT was first prepared by simply mixing boron nitride in a solution of rhodium acetate, under inert atmosphere for a week followed by filtration (yield: 92%). The catalyst can be re-used for up to four times and showed minimal loss of activity...
January 2017: Journal of Photochemistry and Photobiology. B, Biology
Subhash Chander, Ping Wang, Penta Ashok, Liu-Meng Yang, Yong-Tang Zheng, Murugesan Sankaranarayanan
In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a-n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as well as their drug-likeness behavior was predicted using in-silico studies. All the designed compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory activity, in which tested compounds displayed significant to weak potency against the selected target...
January 1, 2017: Bioorganic & Medicinal Chemistry Letters
Mitra Kheirabadi, Javad Maleki, Safieh Soufian, Samaneh Hosseini
HTLV-1 and HIV-1 are two major causes for severe T-cell leukemia disease and acquired immune deficiency syndrome (AIDS). HTLV-1 protease, a member of aspartic acid protease family, plays important roles in maturation during virus replication cycle. The impairment of these proteases results in uninfectious HTLV-1virions.Similar to HIV-1protease deliberate mutations that confer drug resistance on HTLV-1 are frequently seen in this protease. Therefore, inhibition of HTLV-1 protease activity is expected to disrupt HTLV-1's ability to replicate and infect additional cells...
March 2016: Molecular Biology Research Communications
Seema Patel
Hepatitis C (HCV) is a deadly virus from family Flaviviridae, causing acute or chronic liver inflammation. Given its lethality and no known vaccine to curb it, understanding its pathogenic mechanism is critical. By analyzing the domains in its protein sequence, a plethora can be learnt about its immune manipulation strategies. In this regard, current in silico study compares publicly-available HCV polyprotein sequences and their domain profiles. Apart from using UniProt sequences and SMART (Simple modular architecture research tool) platform for domain profiling, a set of customized scripts were developed to extract the patterns of protein domain distribution...
October 15, 2016: Computational Biology and Chemistry
Yohannes W Woldeamanuel, Peter R Kamerman, Demetri G A Veliotes, Tudor J Phillips, David Asboe, Marta Boffito, Andrew S C Rice
HIV-associated sensory peripheral neuropathy (HIV-SN) afflicts approximately 50% of patients on antiretroviral therapy, and is associated with significant neuropathic pain. Simple accurate diagnostic instruments are required for clinical research and daily practice in both high- and low-resource setting. A 4-item clinical tool (CHANT: Clinical HIV-associated Neuropathy Tool) assessing symptoms (pain and numbness) and signs (ankle reflexes and vibration sense) was developed by selecting and combining the most accurate measurands from a deep phenotyping study of HIV positive people (Pain In Neuropathy Study-HIV-PINS)...
2016: PloS One
Saghi Sepehri, Lotfollah Saghaie, Afshin Fassihi
The fusion of viral and host cell membranes is mediated using gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. As the HIV-1 enters the host cells, the two helical regions (HR1 and HR2) in the ectodomain of gp41 form a six-helix bundle, which carries the target and viral cell membranes to close proximity. Steps of this process serve as attractive targets for developing HIV-1 fusion inhibitors. Identification of some novel HIV fusion inhibitors with the goal of blocking the formation of the six-helix bundle was accomplished by computer-aided drug design techniques...
October 12, 2016: Molecular Informatics
Qiang Shao
Large-scale conformational changes in proteins are important for their functions. Tracking the conformational change in real time at the level of a single protein molecule, however, remains a great challenge. In this article, we present a novel in silico approach with the combination of normal mode analysis and integrated-tempering-sampling molecular simulation (NMA-ITS) to give quantitative data for exploring the conformational transition pathway in multi-dimensional energy landscapes starting only from the knowledge of the two endpoint structures of the protein...
October 12, 2016: Physical Chemistry Chemical Physics: PCCP
Ann Baeyens, Evelien Naessens, Anouk Van Nuffel, Karin E Weening, Anne-Marie Reilly, Eva Claeys, Wim Trypsteen, Linos Vandekerckhove, Sven Eyckerman, Kris Gevaert, Bruno Verhasselt
To facilitate studies on Vpr function in replicating HIV-1, we aimed to tag the protein in an infectious virus. First we showed that N-, but not C-terminal HA/FLAG tagging of Vpr protein preserves Vpr cytopathicity. Cloning the tags into proviral DNA however ablated viral production and replication. By construction of additional viral variants we could show this defect was not protein- but RNA-dependent and sequence specific, and characterized by oversplicing of the genomic RNA. Simulation of genomic RNA folding suggested that introduction of the tag sequence induced an alternative folding structure in a region enriched in splice sites and splicing regulatory sequences...
October 10, 2016: Scientific Reports
Francesca Moraca, Kriti Acharya, Bruno Melillo, Amos B Smith, Irwin Chaiken, Cameron F Abrams
Small-molecule CD4 mimics (SMCM's) bind to the gp120 subunit of the HIV-1 envelope glycoprotein (Env) and have been optimized to block cell infection in vitro. The lack of the V1/2 and V3 loops and the presence of the β2/3 and β20/21 strands (bridging sheet) in the available structures of the monomeric gp120 core may limit its applicability as a target for further synthetic optimization of SMCM potency and/or breadth. Here, we employ a combination of binding-site search, docking, estimation of protein-ligand interaction energy, all-atom molecular dynamics, and ELISA-based CD4-binding competition assays to create, characterize, and rationalize models of first- and second-generation of SMCM's bound to the distinct, trimeric BG505 SOSIP...
October 24, 2016: Journal of Chemical Information and Modeling
Loris Moretti, Luca Sartori
In the field of Computer-Aided Drug Discovery and Development (CADDD) the proper software infrastructure is essential for everyday investigations. The creation of such an environment should be carefully planned and implemented with certain features in order to be productive and efficient. Here we describe a solution to integrate standard computational services into a functional unit that empowers modelling applications for drug discovery. This system allows users with various level of expertise to run in silico experiments automatically and without the burden of file formatting for different software, managing the actual computation, keeping track of the activities and graphical rendering of the structural outcomes...
September 2016: Molecular Informatics
Fatima E Agharbaoui, Ashley C Hoyte, Stefania Ferro, Rosaria Gitto, Maria Rosa Buemi, James R Fuchs, Mamuka Kvaratskhelia, Laura De Luca
Through structure-based virtual screening and subsequent activity assays of selected natural products, Lavendustin B was previously identified as an inhibitor of HIV-1 integrase (IN) interaction with its cognate cellular cofactor, lens epithelium-derived growth factor (LEDGF/p75). In order to improve the inhibitory potency we have employed in silico-based approaches. Particularly, a series of new analogues was designed and docked into the LEDGF/p75 binding pocket of HIV-1 IN. To identify promising leads we used the Molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation (MM-GBSA) method, molecular dynamics simulations and analysis of hydrogen bond occupancies...
November 10, 2016: European Journal of Medicinal Chemistry
G Luca Gusella, Avelino Teixeira, Judith Aberg, Vladimir N Uversky, Arevik Mosoian
BACKGROUND: Prothymosin α (ProTα) (isoform 2: iso2) is a widely distributed, small acidic protein with intracellular and extracellular-associated functions. Recently, we identified two new ProTα variants with potent anti-HIV activity from CD8+ T cells and cervicovaginal lavage. The first is a splice variant of the ProTα gene known as isoB and the second is the product of ProTα pseudogene 7 (p7). Similarly to iso2, the anti-HIV activity of both variants is mediated by type I IFN. Here we tested whether the immunomodulatory activity of isoB and p7 are also TLR4 dependent and determined their kinetic of release in response to HIV-1 infection...
2016: PloS One
Juliana Gonçalves, Elsa Moreira, Inês J Sequeira, António S Rodrigues, José Rueff, Aldina Brás
Chromosomal fragile sites (FSs) are loci where gaps and breaks may occur and are preferential integration targets for some viruses, for example, Hepatitis B, Epstein-Barr virus, HPV16, HPV18, and MLV vectors. However, the integration of the human immunodeficiency virus (HIV) in Giemsa bands and in FSs is not yet completely clear. This study aimed to assess the integration preferences of HIV in FSs and in Giemsa bands using an in silico study. HIV integration positions from Jurkat cells were used and two nonparametric tests were applied to compare HIV integration in dark versus light bands and in FS versus non-FS (NFSs)...
2016: International Journal of Genomics
Kanupriya Tiwari, Salma Jamal, Sonam Grover, Sukriti Goyal, Aditi Singh, Abhinav Grover
BACKGROUND: Tuberculosis is the second leading cause of death from an infectious disease worldwide after HIV, thus reasoning the expeditions in anti-tuberculosis research. The rising number of cases of infection by resistant forms of M. tuberculosis has given impetus to the development of novel drugs that have different targets and mechanisms of action against the bacterium. METHODS: In this study, we have used machine learning algorithms on the available high throughput screening data of inhibitors of fructose bisphosphate aldolase, an enzyme central to the glycolysis pathway in M...
June 9, 2016: Combinatorial Chemistry & High Throughput Screening
Emiliene Berinyuy, Mahmoud E S Soliman
Inhibition of HIV-1 target cell entry, by targeting gp120, has been identified as a promising approach for the identification and development of prophylactic and salvage HIV infection inhibitors. A small molecule compound 18A is an important chemotype in the development of novel and diverse viral cell entry inhibitors, as it inhibits a wide variety of HIV strains by disrupting allosteric structuring on gp120. This study combines residue energy contribution (REC) pharmacophore mapping of 18A and in silico molecular docking in a virtual screening campaign to identify novel and diverse antagonists of gp120...
May 10, 2016: Interdisciplinary Sciences, Computational Life Sciences
Birgit Viira, Anastasia Selyutina, Alfonso T García-Sosa, Maarit Karonen, Jari Sinkkonen, Andres Merits, Uko Maran
A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested...
June 1, 2016: Bioorganic & Medicinal Chemistry
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