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      Large-scale computational drug repositioning to find treatments for rare diseases

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          Abstract

          Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

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          AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.

          We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique. (c) 2009 Wiley Periodicals, Inc.
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            Comparison of the predicted and observed secondary structure of T4 phage lysozyme.

            Predictions of the secondary structure of T4 phage lysozyme, made by a number of investigators on the basis of the amino acid sequence, are compared with the structure of the protein determined experimentally by X-ray crystallography. Within the amino terminal half of the molecule the locations of helices predicted by a number of methods agree moderately well with the observed structure, however within the carboxyl half of the molecule the overall agreement is poor. For eleven different helix predictions, the coefficients giving the correlation between prediction and observation range from 0.14 to 0.42. The accuracy of the predictions for both beta-sheet regions and for turns are generally lower than for the helices, and in a number of instances the agreement between prediction and observation is no better than would be expected for a random selection of residues. The structural predictions for T4 phage lysozyme are much less successful than was the case for adenylate kinase (Schulz et al. (1974) Nature 250, 140-142). No one method of prediction is clearly superior to all others, and although empirical predictions based on larger numbers of known protein structure tend to be more accurate than those based on a limited sample, the improvement in accuracy is not dramatic, suggesting that the accuracy of current empirical predictive methods will not be substantially increased simply by the inclusion of more data from additional protein structure determinations.
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              DrugBank: a comprehensive resource for in silico drug discovery and exploration

              DrugBank is a unique bioinformatics/cheminformatics resource that combines detailed drug (i.e. chemical) data with comprehensive drug target (i.e. protein) information. The database contains >4100 drug entries including >800 FDA approved small molecule and biotech drugs as well as >3200 experimental drugs. Additionally, >14 000 protein or drug target sequences are linked to these drug entries. Each DrugCard entry contains >80 data fields with half of the information being devoted to drug/chemical data and the other half devoted to drug target or protein data. Many data fields are hyperlinked to other databases (KEGG, PubChem, ChEBI, PDB, Swiss-Prot and GenBank) and a variety of structure viewing applets. The database is fully searchable supporting extensive text, sequence, chemical structure and relational query searches. Potential applications of DrugBank include in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. DrugBank is available at .
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                Author and article information

                Contributors
                +(225) 578-2791 , michal@brylinski.org
                Journal
                NPJ Syst Biol Appl
                NPJ Syst Biol Appl
                NPJ Systems Biology and Applications
                Nature Publishing Group UK (London )
                2056-7189
                13 March 2018
                13 March 2018
                2018
                : 4
                : 13
                Affiliations
                [1 ]ISNI 0000 0001 0662 7451, GRID grid.64337.35, Department of Biological Sciences, , Louisiana State University, ; Baton Rouge, LA 70803 USA
                [2 ]ISNI 0000 0001 0662 7451, GRID grid.64337.35, Division of Computer Science and Engineering, , Louisiana State University, ; Baton Rouge, LA 70803 USA
                [3 ]ISNI 0000 0001 0662 7451, GRID grid.64337.35, Center for Computation and Technology, , Louisiana State University, ; Baton Rouge, LA 70803 USA
                Author information
                http://orcid.org/0000-0001-9866-5366
                http://orcid.org/0000-0002-6204-2869
                Article
                50
                10.1038/s41540-018-0050-7
                5847522
                29560273
                7b7824d8-4e58-4653-a66e-ca6057969460
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 November 2017
                : 22 January 2018
                : 3 February 2018
                Categories
                Technology Feature
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                © The Author(s) 2018

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