Evaluation of Protein-Ligand binding interactions of alkaline phosphatase inhibitors by Quantum-Mechanical methods

Quantum-mechanical (QM) methods were applied to compute the relative binding energies of a set of structurally similar alkaline phosphatase (AP) inhibitors, using human placental AP (PLAP) as a model AP. The theoretical binding affinities were compared with their corresponding experimental inhibitory potencies. The calculated interaction energies reproduced the experimental activity order, showing linear correlations between QM relative binding energies and experimental pIC₅₀ values with coefficients of determination R² = 0.86-0.97. Examination of the binding interactions for the test inhibitors revealed that the AP inhibitory activity is determined by the catechol group and the benzimidazole/imidazole moieties of the ligands. The studied compounds formed protein-ligand complexes inside the active site of PLAP, suggesting they are competitive inhibitors. The present theoretical results are expected to be useful in developing new potent AP inhibitors. The employed computational approach for estimating QM protein - ligand interaction energies is proposed as a suitable drug design tool for predicting reliable QM relative binding affinities of structurally related compounds.