Investigation of Mutant GFAP Protein Associated with Alexander Disease and its Therapeutic Intervention: Structure Based Drug Design Approach

Systems Biology approach involves integration of experimental and computational research to understand complex biological systems. Alexander's Disease (AxD) was first described by W. S. Alexander in 1949, and is a rare, but often fatal neurological disorder that has been divided into three subtypes based on the age of onset: the infantile, juvenile and adult forms that are shown to be caused by mutations in the gfap gene. The infantile form, with onset between birth and about two years of age, is currently the most common form of the disease. The characteristic neuropathological feature of all forms of AxD is the presence of Rosenthal fibers. In present study, the mutant GFAP protein associated with AxD was investigated by predicting the structure of wild type and mutant GFAP protein. It was found that due to the reported single point mutation, the mutant protein adopted a left handed α-helix structure in sharp contrast to the predicted right handed α-helix of the wt GFAP indicating large conformational change which may be the cause of aggregation of GFAP forming Rosenthal Fibers. In the absence of any commercially available drug to alleviate the symptoms of AxD, the therapeutic intervention of mutant GFAP protein was done using structure based drug design approach. The drug dibutyryl cyclic AMP identified through data mining from STITCH 4.0 was found to be toxic and therefore its structural analogs were generated using GAUSSIAN 09. Each of the 20 structural analogs of dbcAMP were docked with mutant GFAP using Discovery Studio 2.5 and analysed for their toxicity potential using OSIRIS Property Explorer. Three structural analogs i.e. DBCM12, DBCM17 and DBCM20 were found to have favourable docking, druglikeness and did not pose any toxicity risk. These structural analogs identified may be further analysed for therapeutic intervention of AxD by their role in prevention of aggregation of mutant GFAP.

In silico design of small molecules targeting cathepsin-k for the treatment of osteoarthritis

Purpose: To investigate cathespin-K as an alternative drug target for the development of a new therapy for osteoarthritis (OA) in humans.Method:  In silico molecular docking simulation-based virtual screening was used to identify probable lead molecules with significant binding affinities for the target receptor, and acceptable pharmacokinetic profiling. Lamarkian genetic algorithm was used for molecular docking simulation, while various physicochemical parameters such as molecular weight, calculated partition coefficient, topological polar surface area, and hydrogen bond acceptor and donor counts were evaluated for their pharmacokinetic profile.Results: The compound, ZINC05386901, was found to be a potent inhibitor of human cathespin-K protein with excellent pharmacokinetic properties, and had no toxic effects.Conclusion: The designed inhibitor molecule for cathespin-K protein is a promising lead molecule for further structure-based discovery of novel drugs for the treatment of OA.Keywords: Osteoarthritis, Cathepsin-K, Drug design, Ligan

In-silico design of novel myocilin inhibitors for glaucoma therapy

Purpose: To explore newer computational approaches in the design of novel myocilin inhibitors for the treatment of glaucoma.Methods: An in-silico virtual screening technique based on simulation of molecular docking was utilised to design a novel myocilin inhibitors for the treatment of  glaucoma. The designed novel molecules were theoretically evaluated to predict their pharmacokinetic properties and toxic effects. Lead molecules were screened out in virtual screening technique on the basis of low binding energies obtained in AutoDock based molecular docking simulation.Results: Out of ten top lead compounds screened, ZINC01729523 and ZINC04692015 were promising, having shown potent inhibition of myocilin, good pharmacokinetic properties and absence of any toxic effects.Conclusion: In-silico virtual screening of molecular libraries containing a large number of ligands is very useful for short-listing of potential lead molecules for further structure-based discovery of antiglaucoma-drugs.Keywords: Glaucoma, Myocilin, Docking, Virtual-screening, Autodock, Ligand, Drug desig

Anthelmintic Activity In Vivo of Epiisopiloturine against Juvenile and Adult Worms of Schistosoma mansoni

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported

Anthelmintic Activity In Vivo Of Epiisopiloturine Against Juvenile And Adult Worms Of Schistosoma Mansoni

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported.93Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundacao para a Ciencia e a Tecnologia (FCT) [PEst-C/EQB/LA0006/2011, PTDC/CTM-NAN/109877/2009]Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Faculdade de Ciencias de Guarulhos FACIG/UNIESPConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Ministry of Education, Science, and Technological Development of Serbia [172008]Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CAPES [705/2009]CNPq [490585/2010-8]CNPq [40/2012, 404134/2012-2

Review of QSAR Models and Software Tools for Predicting Developmental and Reproductive Toxicity

This report provides a state-of-the-art review of available computational models for developmental and reproductive toxicity, including Quantitative Structure-Activity Relationship (QSARs) and related estimation methods such as decision tree approaches and expert systems. At present, there are relatively few models for developmental and reproductive toxicity endpoints, and those available have limited applicability domains. This situation is partly due to the biological complexity of the endpoint, which covers many incompletely understood mechanisms of action, and partly due to the paucity and heterogeneity of high quality data suitable for model development. In contrast, there is an extensive and growing range of software and literature models for predicting endocrine-related activities, in particular models for oestrogen and androgen activity. There is a considerable need to further develop and characterise in silico models for developmental and reproductive toxicity, and to explore their applicability in a regulatory setting.JRC.DG.I.6-Systems toxicolog

Synthesis of coumarins linked with 1,2,3-triazoles under microwave irradiation and evaluation of their antimicrobial and antioxidant activity

A series of coumarin derivatives linked with 1,2,3-triazoles has been synthesized by utilizing the copper catalyzed azide-alkyne cycloaddition reaction and were screened for their antimicrobial and antioxidant properties. Some of the compounds displayed promising antibacterial activities (MIC ranging from 5-150 µg/mL) and moderate antifungal activities as compared to the respective standards. The compounds 4k and 4g displayed good antibacterial activity when compared with the standard, Ciprofloxacin, and 4n exhibited better antifungal activity when compared to other synthesized compounds. The in silico docking studies of the active compounds were carried out against the gyrase enzyme and from those studies, it was acknowledged that 4k possessed significant hydrogen bonding and hydrophobic interactions which could be the plausible reason for its superior activity as compared to the other synthesized compounds. The compounds 4h and 4q showed promising antioxidant activity when compared with the standard, BHT, which could be attributed to the presence of electron donating substituents. © 2020, Sociedad Química de México.Russian Foundation for Basic Research, RFBR: 170300641AThe authors are thankful to the Department of Industrial Chemistry, Kuvempu University for rendering all the facilities to carry out the experiments. Vasiliy Bakulev is thankful to Russian Foundation for Basic Research (Grant # 170300641A)

Information retrieval and text mining technologies for chemistry

Efficient access to chemical information contained in scientific literature, patents, technical reports, or the web is a pressing need shared by researchers and patent attorneys from different chemical disciplines. Retrieval of important chemical information in most cases starts with finding relevant documents for a particular chemical compound or family. Targeted retrieval of chemical documents is closely connected to the automatic recognition of chemical entities in the text, which commonly involves the extraction of the entire list of chemicals mentioned in a document, including any associated information. In this Review, we provide a comprehensive and in-depth description of fundamental concepts, technical implementations, and current technologies for meeting these information demands. A strong focus is placed on community challenges addressing systems performance, more particularly CHEMDNER and CHEMDNER patents tasks of BioCreative IV and V, respectively. Considering the growing interest in the construction of automatically annotated chemical knowledge bases that integrate chemical information and biological data, cheminformatics approaches for mapping the extracted chemical names into chemical structures and their subsequent annotation together with text mining applications for linking chemistry with biological information are also presented. Finally, future trends and current challenges are highlighted as a roadmap proposal for research in this emerging field.A.V. and M.K. acknowledge funding from the European Community’s Horizon 2020 Program (project reference: 654021 - OpenMinted). M.K. additionally acknowledges the Encomienda MINETAD-CNIO as part of the Plan for the Advancement of Language Technology. O.R. and J.O. thank the Foundation for Applied Medical Research (FIMA), University of Navarra (Pamplona, Spain). This work was partially funded by Consellería de Cultura, Educación e Ordenación Universitaria (Xunta de Galicia), and FEDER (European Union), and the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684). We thank Iñigo Garciá -Yoldi for useful feedback and discussions during the preparation of the manuscript.info:eu-repo/semantics/publishedVersio