A reliable docking/scoring scheme based on the semiempirical quantum mechanical PM6-DH2 method accurately covering dispersion and H-bonding: HIV-1 protease with 22 ligands
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20839830
DOI
10.1021/jp1032965
Knihovny.cz E-resources
- MeSH
- HIV-1 enzymology MeSH
- HIV Protease chemistry MeSH
- Quantum Theory MeSH
- Humans MeSH
- Ligands * MeSH
- Computer Simulation MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Hydrogen Bonding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HIV Protease MeSH
- Ligands * MeSH
- p16 protease, Human immunodeficiency virus 1 MeSH Browser
In this study, we introduce a fast and reliable rescoring scheme for docked complexes based on a semiempirical quantum mechanical PM6-DH2 method. The method utilizes a PM6-based Hamiltonian with corrections for dispersion energy and hydrogen bonds. The total score is constructed as the sum of the PM6-DH2 interaction enthalpy, the empirical force field (AMBER) interaction entropy, and the sum of the deformation (PM6-DH2, SMD) and the desolvation (SMD) energies of the ligand. The main advantage of the procedure is the fact that we do not add any empirical parameter for either an individual component of the total score or an individual protein-ligand complex. This rescoring method is applied to a very challenging system, namely, the HIV-1 protease with a set of ligands. As opposed to the conventional DOCK procedure, the PM6-DH2 rescoring based on all of the terms distinguishes between binders and nonbinders and provides a reliable correlation of the theoretical and experimental binding free energies. Such a dramatic improvement, resulting from the PM6-DH2 rescoring of all the complexes, provides a valuable yet inexpensive tool for rational drug discovery and de novo ligand design.
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