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      Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels

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          Abstract

          Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (Na V). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria. In contrast, toxins of the TTX group occur mainly in macrozoa, particularly among puffer fish, several species of marine invertebrates and a few terrestrial amphibians. In the case of TTX and analogs, most evidence suggests that symbiotic bacteria are the origin of the toxins, although endogenous biosynthesis independent from bacteria has not been excluded. The evolutionary origin of the biosynthetic genes for STX and analogs in dinoflagellates and cyanobacteria remains elusive. These highly potent molecules have been the subject of intensive research since the latter half of the past century; first to study the mode of action of their toxigenicity, and later as tools to characterize the role and structure of Na V channels, and finally as therapeutics. Their pharmacological activities have provided encouragement for their use as therapeutants for ion channel-related pathologies, such as pain control. The functional role in aquatic and terrestrial ecosystems for both groups of toxins is unproven, although plausible mechanisms of ion channel regulation and chemical defense are often invoked. Molecular approaches and the development of improved detection methods will yield deeper understanding of their physiological and ecological roles. This knowledge will facilitate their further biotechnological exploitation and point the way towards development of pharmaceuticals and therapeutic applications.

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          A review of harmful algal blooms and their apparent global increase*

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            A critical assessment of docking programs and scoring functions.

            Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.
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              Major increases in opioid analgesic abuse in the United States: concerns and strategies.

              The problem of abuse of and addiction to opioid analgesics has emerged as a major issue for the United States in the past decade and has worsened over the past few years. The increases in abuse of these opioids appear to reflect, in part, changes in medication prescribing practices, changes in drug formulations as well as relatively easy access via the internet. Though the use of opioid analgesics for the treatment of acute pain appears to be generally benign, long-term administration of opioids has been associated with clinically meaningful rates of abuse or addiction. Important areas of research to help with the problem of opioid analgesic abuse include the identification of clinical practices that minimize the risks of addiction, the development of guidelines for early detection and management of addiction, the development of opioid analgesics that minimize the risks for abuse, and the development of safe and effective non-opioid analgesics. With high rates of abuse of opiate analgesics among teenagers in the United States, a particularly urgent priority is the investigation of best practices for treating pain in adolescents as well as the development of prevention strategies to reduce diversion and abuse.
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                Author and article information

                Journal
                Mar Drugs
                Mar Drugs
                marinedrugs
                Marine Drugs
                MDPI
                1660-3397
                13 October 2017
                October 2017
                : 15
                : 10
                Affiliations
                [1 ]CONACYT—Instituto de Ciencias del Mary Limnología, Universidad Nacional Autónoma de México, Mexico 04510, Mexico
                [2 ]Alfred-Wegener-Institut, Helmholtz Zentrum für Polar-und Meeresforschung, 27570 Bremerhaven, Germany; Allan.Cembella@ 123456awi.de
                Author notes
                [* ]Correspondence: lduran@ 123456conacyt.mx ; Tel.: +52-55-5623-0222 (ext. 44639)
                Article
                marinedrugs-15-00303
                10.3390/md15100303
                5666411
                29027912
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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