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Transition state-based ST6Gal I inhibitors: Mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation

Journal Article


Abstract


  • Human β-galactoside α-2,6-sialyltransferase I (ST6Gal I) catalyses the synthesis of sialylated glycoconjugates. Overexpression of ST6Gal I is observed in many cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase inhibitors have been developed, with analogues structurally similar to the transition state exhibiting the highest inhibitory activity. To improve synthetic accessibility and pharmacokinetics of previously reported inhibitors, the replacement of the charged phosphodiester linker with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been investigated. Extensive molecular dynamics simulations have demonstrated that compounds with the alternate linkers could maintain key interactions with the human ST6Gal I active site, demonstrating the potential of a carbamate or a 1,2,3-triazole as a phosphodiester isostere. Free energy perturbation calculations provided energetic evidence suggesting that the carbamate and 1,2,3-triazole were slightly more favourable than the phosphodiester. Further exploration with free energy component, quasi-harmonic and cluster analysis suggested that there is an enthalpy-entropy compensation accounting for the replacement of the flexible charged phosphodiester with a neutral and rigid isostere. Overall, these simulations provide a strong rationale for the use of a carbamate or 1,2,3-triazole as a phosphodiester isostere in the development of novel inhibitors of human ST6Gal I.

Publication Date


  • 2017

Citation


  • Montgomery, A. P., Skropeta, D. & Yu, H. (2017). Transition state-based ST6Gal I inhibitors: Mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation. Scientific Reports, 7 (1), 14428-1-14428-11.

Scopus Eid


  • 2-s2.0-85032644741

Start Page


  • 14428-1

End Page


  • 14428-11

Volume


  • 7

Issue


  • 1

Place Of Publication


  • United Kingdom

Abstract


  • Human β-galactoside α-2,6-sialyltransferase I (ST6Gal I) catalyses the synthesis of sialylated glycoconjugates. Overexpression of ST6Gal I is observed in many cancers, where it promotes metastasis through altered cell surface sialylation. A wide range of sialyltransferase inhibitors have been developed, with analogues structurally similar to the transition state exhibiting the highest inhibitory activity. To improve synthetic accessibility and pharmacokinetics of previously reported inhibitors, the replacement of the charged phosphodiester linker with a potential neutral isostere such as a carbamate or a 1,2,3-triazole has been investigated. Extensive molecular dynamics simulations have demonstrated that compounds with the alternate linkers could maintain key interactions with the human ST6Gal I active site, demonstrating the potential of a carbamate or a 1,2,3-triazole as a phosphodiester isostere. Free energy perturbation calculations provided energetic evidence suggesting that the carbamate and 1,2,3-triazole were slightly more favourable than the phosphodiester. Further exploration with free energy component, quasi-harmonic and cluster analysis suggested that there is an enthalpy-entropy compensation accounting for the replacement of the flexible charged phosphodiester with a neutral and rigid isostere. Overall, these simulations provide a strong rationale for the use of a carbamate or 1,2,3-triazole as a phosphodiester isostere in the development of novel inhibitors of human ST6Gal I.

Publication Date


  • 2017

Citation


  • Montgomery, A. P., Skropeta, D. & Yu, H. (2017). Transition state-based ST6Gal I inhibitors: Mimicking the phosphodiester linkage with a triazole or carbamate through an enthalpy-entropy compensation. Scientific Reports, 7 (1), 14428-1-14428-11.

Scopus Eid


  • 2-s2.0-85032644741

Start Page


  • 14428-1

End Page


  • 14428-11

Volume


  • 7

Issue


  • 1

Place Of Publication


  • United Kingdom