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Crystal structures of nematode (parasitic T. spiralis and free living C. elegans), compared to mammalian, thymidylate synthases (TS). Molecular docking and molecular dynamics simulations in search for nematode-specific inhibitors of TS

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dc.abstract.enThree crystal structures are presented of nematode thymidylate synthases (TS), including Caenorhabditis elegans (Ce) enzyme without ligands and its ternary complex with dUMP and Raltitrexed, and binary complex of Trichinella spiralis (Ts) enzyme with dUMP. In search of differences potentially relevant for the development of species-specific inhibitors of the nematode enzyme, a comparison was made of the present Ce and Ts enzyme structures, as well as binary complex of Ce enzyme with dUMP, with the corresponding mammalian (human, mouse and rat) enzyme crystal structures. To complement the comparison, tCONCOORD computations were performed to evaluate dynamic behaviors of mammalian and nematode TS structures. Finally, comparative molecular docking combined with molecular dynamics and free energy of binding calculations were carried out to search for ligands showing selective affinity to T. spiralis TS. Despite an overall strong similarity in structure and dynamics of nematode vs mammalian TSs, a pool of ligands demonstrating predictively a strong and selective binding to TsTS has been delimited. These compounds, the E63 family, locate in the dimerization interface of TsTS where they exert species specific interactions with certain non-conserved residues, including hydrogen bonds with Thr174 and hydrophobic contacts with Phe192, Cys191 and Tyr152. The E63 family of ligands opens the possibility of future development of selective inhibitors of TsTS and effective agents against trichinellosis. (C) 2017 Elsevier Inc. All rights reserved.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMaj, Piotr
dc.contributor.authorWilk, Piotr
dc.contributor.authorBronowska, Agnieszka
dc.contributor.authorDowierciał, Anna
dc.contributor.authorFilipek, Sławomir
dc.contributor.authorRODE, WOJCIECH
dc.contributor.authorJARMUŁA, ADAM
dc.contributor.authorRypniewski, Wojciech
dc.contributor.authorLudwiczak, Jan
dc.contributor.authorDĄBROWSKA, MAGDALENA
dc.contributor.authorJakowiecki, Jakub
dc.contributor.authorBanaszak, Katarzyna
dc.contributor.authorFrączyk, Tomasz
dc.contributor.authorCieśla, Joanna
dc.date.accessioned2024-01-24T20:55:48Z
dc.date.available2024-01-24T20:55:48Z
dc.date.issued2017
dc.description.financeNie dotyczy
dc.description.volume77
dc.identifier.doi10.1016/J.JMGM.2017.08.008
dc.identifier.issn1093-3263
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/103993
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/abs/pii/S109332631730462X?via%3Dihub
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofJournal of Molecular Graphics and Modelling
dc.relation.pages33-50
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enThymidylate synthase (TS)
dc.subject.enCrystal structures
dc.subject.enMolecular docking
dc.subject.enInhibitors of Trichinella spiralis
dc.titleCrystal structures of nematode (parasitic T. spiralis and free living C. elegans), compared to mammalian, thymidylate synthases (TS). Molecular docking and molecular dynamics simulations in search for nematode-specific inhibitors of TS
dc.typeJournalArticle
dspace.entity.typePublication