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Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design

Journal Article


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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.

Publication Date


  • 2016

Citation


  • Montgomery, A., Szabo, R., Skropeta, D. & Yu, H. (2016). Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design. Journal of Molecular Recognition, 29 (5), 210-222.

Scopus Eid


  • 2-s2.0-84949945795

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4599&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3576

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 210

End Page


  • 222

Volume


  • 29

Issue


  • 5

Place Of Publication


  • United Kingdom

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.

Publication Date


  • 2016

Citation


  • Montgomery, A., Szabo, R., Skropeta, D. & Yu, H. (2016). Computational characterisation of the interactions between human ST6Gal I and transition-state analogue inhibitors: insights for inhibitor design. Journal of Molecular Recognition, 29 (5), 210-222.

Scopus Eid


  • 2-s2.0-84949945795

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=4599&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/3576

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 210

End Page


  • 222

Volume


  • 29

Issue


  • 5

Place Of Publication


  • United Kingdom