New generation of docking programs: Supercomputer validation offorce fields and quantum-chemical methods for dockingстатья

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1. Графический абстракт graphical_abstract.pdf 404,3 КБ 15 ноября 2017 [DanilKutov]

[1] New generation of docking programs: Supercomputer validation offorce fields and quantum-chemical methods for docking / A. V. Sulimov, D. C. Kutov, E. V. Katkova et al. // Journal of Molecular Graphics and Modelling. — 2017. — Vol. 78, no. November 2017. — P. 139–147. Discovery of new inhibitors of the protein associated with a given disease is the initial and most importantstage of the whole process of the rational development of new pharmaceutical substances. New inhibitorsblock the active site of the target protein and the disease is cured. Computer-aided molecular modelingcan considerably increase effectiveness of new inhibitors development. Reliable predictions of the targetprotein inhibition by a small molecule, ligand, is defined by the accuracy of docking programs. Such pro-grams position a ligand in the target protein and estimate the protein-ligand binding energy. Positioningaccuracy of modern docking programs is satisfactory. However, the accuracy of binding energy calcula-tions is too low to predict good inhibitors. For effective application of docking programs to new inhibitorsdevelopment the accuracy of binding energy calculations should be higher than 1 kcal/mol. Reasons oflimited accuracy of modern docking programs are discussed. One of the most important aspects limitingthis accuracy is imperfection of protein-ligand energy calculations. Results of supercomputer validationof several force fields and quantum-chemical methods for docking are presented. The validation wasperformed by quasi-docking as follows. First, the low energy minima spectra of 16 protein-ligand com-plexes were found by exhaustive minima search in the MMFF94 force field. Second, energies of the lowest8192 minima are recalculated with CHARMM force field and PM6-D3H4X and PM7 quantum-chemicalmethods for each complex. The analysis of minima energies reveals the docking positioning accuraciesof the PM7 and PM6-D3H4X quantum-chemical methods and the CHARMM force field are close to oneanother and they are better than the positioning accuracy of the MMFF94 force field. [ DOI ]

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