Application of the PM7 quantum chemical semi-empirical method to the development of new urokinase inhibitors

E. V. Katkova ; I. V. Oferkin ; V. B. Sulimov

Numerical methods and programming, Tome 15 (2014) no. 2, pp. 258-273.

Résumé

The application of quantum-chemistry semi-empirical methods using the MOPAC programs to the search for new inhibitors is considered. The best operating conditions for the PM7 parameterization method in the framework of MOPAC are studied. This method allows taking into account various noncovalent intermolecular interactions, such as dispersion interactions and halogen and hydrogen bonds. It is shown that different methods of protein protonation have a great influence on the protein-ligand binding enthalpies. As a consequence, the hydrogen mobility of the protein plays an important role during the local optimization of the complex. Using the set of 22 different protein-ligand complexes, the importance of the solvent is demonstrated; it is also shown that the correlation coefficients between computed and experimental energies are better for quantum chemical calculations than for the MMFF94 force field calculations for this set. The protein-inhibitor binding enthalpies for native urokinase complexes from the PDB database are calculated, and the correlation coefficients between MOPAC calculations and experiments are found. Some results of MOPAC usage for new urokinase inhibitors design are discussed.

Détail

Keywords: molecular modeling, quantum chemistry, semi-empirical methods, new inhibitors design, optimal operating parameters, grid docking, direct docking.
Mots-clés : efficacy