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.
Highlights
Sialic acid (N-acetylneuraminic acid, Neu5Ac) is one of the body’s most important sugars next to glucose[1]
Large root-mean-square fluctuations (RMSF) values were observed for the regions between Gln235—Asn[250] and Ser260—Ile[295], which comprise the portion of the active site that is expected to interact with the sialyl acceptor
There was some variation in ligand position within this active site, which can be seen in the root-mean-square deviations (RMSD) values that correspond to the heavy atoms of each ligand
Summary
Sialic acid (N-acetylneuraminic acid, Neu5Ac) is one of the body’s most important sugars next to glucose[1]. The catalytic mechanism of human ST6Gal I (Fig. 1) follows a classical SN2-like direct displacement mechanism for inverting GTs11,22 It is facilitated by the catalytic base His[370], which promotes the nucleophilic attack on the sialyl donor anomeric carbon by deprotonating the galactose 6ʹ-hydroxyl of the acceptor[23,24]. This generates an oxocarbenium-like transition state (TS), followed by CMP acting as a leaving group. The β-configuration at the anomeric carbon of the donor is inverted in the final product[24] This is supported by a model of the Michaelis complex generated from the glycan binding mode observed in the crystal structure of human ST6Gal I25
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