Probing the binding mechanism of mercaptoguanine derivatives as inhibitors of HPPK by docking and molecular dynamics simulations

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a promising antimicrobial target involved in the folate biosynthesis pathway. Although, the results from crystallographic studies of HPPK have attracted a great interest in the design of novel HPPK inhibitors, the mechanism of action of HPPK due to inhibitor binding remains questionable. Recently, mercaptoguanine derivatives were reported to inhibit the pyrophosphoryl transfer mechanism of Staphylococcus aureus HPPK (SaHPPK). The present study is an attempt to understand the SaHPPK-inhibitors binding mechanism and to highlight the key residues that possibly involve in the complex formation. To decipher these questions, we used the state-of-the-art advanced insilico approach such as molecular docking, molecular dynamics (MD), molecular mechanics-generalized Born surface area approach. Domain cross correlation and principle component analysis were applied to the snapshots obtained from MD revealed that the compounds with high binding affinity stabilize the conformational dynamics of SaHPPK. The binding free energy estimation showed that the van der Waals and electrostatic interactions played a vital role for the binding mechanism. Additionally, the predicted binding free energy was in good agreement with the experimental values (R² = .78). Moreover, the free energy decomposition on per-residue confirms the key residues that significantly contribute to the complex formation. These results are expected to be useful for rational design of novel SaHPPK inhibitors.