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- W2789306436 abstract "The calculation of electrostatic potential (EP) maps on enzyme-ligand interactions provides critical information regarding substrate affinity and specificity. Here we probed the electrostatic interactions between the orotidine-5'-phosphate decarboxylase (ODCase) active site and the substrate orotidine-5'-monophosphate (OMP), the product uridine-5'-monophosphate (UMP) and two inhibitors, 6-hydroxyuridine-5'-monophosphate (BMP) and xanthosine-5'-monophosphate (XMP), using density functional theory calculations. All four ligands are structurally similar. However, BMP is the strongest known inhibitor of ODCase. The charge distribution in XMP and BMP shared clear similarities with OMP but not UMP. We propose that the resemblance of the EP maps of XMP and BMP to OMP is likely to account for their ability to effectively bind to ODCase and act as potent inhibitors. Using molecular dynamics simulations, we observed that the binding of BMP induced changes in the active site leading to a distribution of additional positive charge not observed in the apo form. In addition, the inhibitor was stabilized by hydrogen bonding interactions between S154 of a loop adjacent to the active site and the N3 and O4 atoms of the hydroxyuridine ring. Based on the EP map calculations, these atoms have the most negative partial charges in comparison to other ligands investigated in this work. The S154/BMP interactions also reduced flexibility of the loop which helped to form a well-defined binding cavity around the ligand. Our calculations showed that the ability of BMP to increase overall positive charge at the enzyme active site combined with the interaction with S154 could explain why BMP is such a potent inhibitor. This work showed how specific electrostatic interactions could improve ligand binding and will aid in the development of future therapeutic inhibitors." @default.
- W2789306436 created "2018-03-29" @default.
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- W2789306436 date "2018-02-01" @default.
- W2789306436 modified "2023-10-16" @default.
- W2789306436 title "Role of Electrostatic Interactions in Ligand Recognition by Orotidine-5’-Monophosphate Decarboxylase (ODCase)" @default.
- W2789306436 doi "https://doi.org/10.1016/j.bpj.2017.11.2304" @default.
- W2789306436 hasPublicationYear "2018" @default.
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