A Computational Simulation Study of Benzamidine Derivatives Binding to Arginine-Specific Gingipain (HRgpA) from Periodontopathogen Porphyromonas gingivalis

We have shown that the binding free energy calculation from molecular dynamics can be adapted successfully to cysteine proteinases, such as arginine-specific gingipain (HRgpA) from Porphyromonas gingivalis. The binding free energy obtained is in good agreement with the available experimental data for eight benzamidine derivatives including urea and ether linker. The calculations showed that the electrostatic energies between HRgpA and inhibitors were important in determining the relative affinities of the inhibitors to the HRgpA, with an average binding free energy of about -5 kcal/mol. The average structures of the eight complexes suggest that benzamidine inhibitors interact with Asp387, His435, and Cys468 by hydrogen bonding and with Trp508 by hydrophilic interactions that are essential for the activities of benzamidine inhibitors. It can therefore be expected that the method provides a reliable tool for the investigation of new HRgpA inhibitors. This finding could significantly benefit the future design of HRgpA inhibitors.