title: Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design.
abstract: Human β-galactoside α-2,6-sialyltransferase I (hST6Gal I) catalyses the synthesis of sialylated glycoconjugates involved in cell-cell interactions. Overexpression of hST6Gal I is observed in many different types of cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase (ST) inhibitors have been developed based on the natural donor, cytidine 5'-monophosphate N-acetylneuraminic acid (CMP-Neu5Ac). Of these, analogues that are structurally similar to the transition state exhibit the highest inhibitory activity. In order to design inhibitors that are readily accessible synthetically and with favourable pharmacokinetic properties, an investigation of the replacement of the charged phosphodiester-linker, present in many ST inhibitors, with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been undertaken. To investigate this, molecular docking and molecular dynamics simulations were performed. These simulations provided an insight into the binding mode of previously reported phosphodiester-linked ST inhibitors and demonstrated that targeting the proposed sialyl acceptor site is a viable option for producing selective inhibitors. The potential for a carbamate- or triazole-linker as an isosteric replacement for the phosphodiester in transition-state analogue ST inhibitors was established using molecular docking. Molecular dynamics simulations of carbamate- and phosphodiester-linked compounds revealed that both classes exhibit consistent interactions with hST6Gal I. Overall, the results obtained from this study provide a rationale for synthetic and biological evaluation of triazole- and carbamate-linked transition-state analogue ST inhibitors as potential new antimetastatic agents.
authors.affiliation: School of Chemistry, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Montgomery
authors.affiliation: School of Chemistry, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Rémi
authors.initials: R
authors.lastname: Szabo
authors.affiliation: School of Chemistry, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.|Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Skropeta
authors.affiliation: School of Chemistry, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, 2522, Australia.|Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry*; D020134:Catalytic Domain / Q000187:drug effects; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D012799:Sialyltransferases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D004791:Enzyme Inhibitors; D014230:Triazoles; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
keywords: inhibitors; metastasis; molecular docking; molecular dynamics simulations; sialyltransferase; transition-state analogues