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

被引:101
作者
Fanfrlik, Jindrich [1 ,2 ]
Bronowska, Agnieszka K. [3 ]
Rezac, Jan [1 ,2 ]
Prenosil, Ondiej [1 ,2 ]
Konvalinka, Jan [1 ,2 ]
Hobza, Pavel [1 ,2 ,4 ]
机构
[1] Acad Sci Czech Republ, Inst Organ Chem & Biochem, Prague 16610 6, Czech Republic
[2] Ctr Biomol & Complex Mol Syst, Prague 16610 6, Czech Republic
[3] Heidelberg Inst Theoret Studies, D-69118 Heidelberg, Germany
[4] Palacky Univ, Dept Phys Chem, Olomouc 77146, Czech Republic
关键词
ORALLY BIOAVAILABLE INHIBITOR; EMPIRICAL SCORING FUNCTION; BINDING-AFFINITY; MOLECULAR-MECHANICS; DRUG-RESISTANCE; FREE-ENERGIES; FORCE-FIELD; PM6; METHOD; DOCKING; DISCOVERY;
D O I
10.1021/jp1032965
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
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-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 13M6-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.
引用
收藏
页码:12666 / 12678
页数:13
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