{"title":"YspD的小分子抗菌配体是对抗小肠结肠炎耶尔森菌感染的潜在治疗剂。","authors":"Debjani Mandal, Raktim Mukherjee, Shrabana Ghosh, Tamanna Bachhawat, Sneha Dutta, Urmisha Das, Abhishek Basu","doi":"10.1007/s40011-022-01443-2","DOIUrl":null,"url":null,"abstract":"<p><p>YspD is a hydrophilic translocator forming the platform for assemblage of functional translocon. Exposure to the extra-cellular milieu makes YspD a potential therapeutic target. DoGSiteScorer predicted best druggable pocket (P0) within YspD, encompassing predominantly the <i>C</i>-terminal helical bundles and the long helices-9 & 5. COACH metaserver also identified ligand binding residues within the aforementioned druggable pocket mapping to helix-9. Amino acids of helix-9 are involved in oligomerization of YspD. Interaction of helix-9 and parts of <i>C</i>-terminal of YspD with hydrophobic translocator protein (YspB), is essential for translocation of bacterial effectors to initiate an infection. Helices-9 & 5 form an intramolecular coiled-coil structure, required for protein-protein interaction. Targeting intramolecular coiled-coil and parts of <i>C</i>-terminal would be important for functional inactivation of YspD. Solvent exposed surface in YspD, particularly in P0, enhances its accessibility to ligands. Nine small molecular inhibitors of TIIISS were identified and retrieved from ZINC15 database (drug-library) as putative drug candidates. Molecular docking of potential ligands with P0 was done using SwissDock server and Achilles Blind Docking server. Considering the \"Significance\" threshold of binding score and region of interaction, Salicylidene Acyl Hydrazide derivatives (INP0400) and Phenoxyacetamide derivative (MBX1641) were found to bind effectively with YspD. These potential ligands interact with functional domains of YspD including parts of <i>C</i>-terminal and the intramolecular coiled-coil, which may affect the oligomerization of YspD and disrupt the interaction of YspD with YspB, inhibiting formation of functional translocon. The identified small molecular antimicrobial ligands of YspD could be tested in vivo to attenuate <i>Y. enterocolitica</i> infection by deregulation of Ysa-Ysp TIIISS.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40011-022-01443-2.</p>","PeriodicalId":54564,"journal":{"name":"Proceedings of the National Academy of Sciences, India. 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COACH metaserver also identified ligand binding residues within the aforementioned druggable pocket mapping to helix-9. Amino acids of helix-9 are involved in oligomerization of YspD. Interaction of helix-9 and parts of <i>C</i>-terminal of YspD with hydrophobic translocator protein (YspB), is essential for translocation of bacterial effectors to initiate an infection. Helices-9 & 5 form an intramolecular coiled-coil structure, required for protein-protein interaction. Targeting intramolecular coiled-coil and parts of <i>C</i>-terminal would be important for functional inactivation of YspD. Solvent exposed surface in YspD, particularly in P0, enhances its accessibility to ligands. Nine small molecular inhibitors of TIIISS were identified and retrieved from ZINC15 database (drug-library) as putative drug candidates. Molecular docking of potential ligands with P0 was done using SwissDock server and Achilles Blind Docking server. Considering the \\\"Significance\\\" threshold of binding score and region of interaction, Salicylidene Acyl Hydrazide derivatives (INP0400) and Phenoxyacetamide derivative (MBX1641) were found to bind effectively with YspD. These potential ligands interact with functional domains of YspD including parts of <i>C</i>-terminal and the intramolecular coiled-coil, which may affect the oligomerization of YspD and disrupt the interaction of YspD with YspB, inhibiting formation of functional translocon. The identified small molecular antimicrobial ligands of YspD could be tested in vivo to attenuate <i>Y. enterocolitica</i> infection by deregulation of Ysa-Ysp TIIISS.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40011-022-01443-2.</p>\",\"PeriodicalId\":54564,\"journal\":{\"name\":\"Proceedings of the National Academy of Sciences, India. 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Small Molecular Antimicrobial Ligands of YspD are Potential Therapeutic Agents Against Yersinia enterocolitica Infection.
YspD is a hydrophilic translocator forming the platform for assemblage of functional translocon. Exposure to the extra-cellular milieu makes YspD a potential therapeutic target. DoGSiteScorer predicted best druggable pocket (P0) within YspD, encompassing predominantly the C-terminal helical bundles and the long helices-9 & 5. COACH metaserver also identified ligand binding residues within the aforementioned druggable pocket mapping to helix-9. Amino acids of helix-9 are involved in oligomerization of YspD. Interaction of helix-9 and parts of C-terminal of YspD with hydrophobic translocator protein (YspB), is essential for translocation of bacterial effectors to initiate an infection. Helices-9 & 5 form an intramolecular coiled-coil structure, required for protein-protein interaction. Targeting intramolecular coiled-coil and parts of C-terminal would be important for functional inactivation of YspD. Solvent exposed surface in YspD, particularly in P0, enhances its accessibility to ligands. Nine small molecular inhibitors of TIIISS were identified and retrieved from ZINC15 database (drug-library) as putative drug candidates. Molecular docking of potential ligands with P0 was done using SwissDock server and Achilles Blind Docking server. Considering the "Significance" threshold of binding score and region of interaction, Salicylidene Acyl Hydrazide derivatives (INP0400) and Phenoxyacetamide derivative (MBX1641) were found to bind effectively with YspD. These potential ligands interact with functional domains of YspD including parts of C-terminal and the intramolecular coiled-coil, which may affect the oligomerization of YspD and disrupt the interaction of YspD with YspB, inhibiting formation of functional translocon. The identified small molecular antimicrobial ligands of YspD could be tested in vivo to attenuate Y. enterocolitica infection by deregulation of Ysa-Ysp TIIISS.
Supplementary information: The online version contains supplementary material available at 10.1007/s40011-022-01443-2.
期刊介绍：
The Proceedings of the National Academy of Sciences, India, Section B: Biological Sciences, is one of the oldest journals of India, launched in the year 1930, by the National Academy of Sciences, India (the Oldest Science Academy of India). The research/review papers of different fields of science, e.g. Agriculture Sciences (Agriculture, Animal Husbandry, Fisheries, Forestry, Agric. Toxicology, Soil Science, Plant Protection, Post Harvest Technology, and Agricultural Engineering), Animal Sciences (Structural, Developmental, Functional, Genetical, Ecological, Behavioural, Taxonomical and Evolutionary Aspects), Biochemistry, Biophysics, Biotechnology (including Molecular and Cell Biology, Structural and Functional Studies, Microbiology and Immunology), Medical & Forensic Sciences (Basic and Clinical Medical Sciences, Pharmacology, Anthropology, Psychology and Forensic Sciences, Human genetics, Reproduction Biology, Neurosciences and Molecular Medicine) and Plant Sciences (Structural, Developmental, Functional, Genetical, Ecological, Taxonomical and Evolutionary Aspects), are published in this journal for dissemination of the scientific knowledge and research. The papers published are indexed/abstracted by the leading abstracting agencies of the world. The papers are published after critical review and editing by the eminent experts of the concerned subject area; therefore, the quality publication is assured once the paper is accepted by the learned referees.
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