Force-field -based methods

Empirical force fields are based on classical mechanics and on the assumption that the conformational and interaction energy of a molecular system can be expressed as a sum of many individual contributions, such as bond-stretching, angle-bending, torsional, electrostatic, and van der Waals interaction terms. While 

The similar MM-GBSA approach has been shown to improve early enrichment rates in the virtual screening of large compound databases [66[. Again, the authors applied only simple energy minimization using the OPLS-AA force field [73] with the generalized Born implicit solvent model. 

Further research in this area might transform MM-PBSA into a useful tool for standard evaluation of binding poses, while advances in computational power might extend applicability of this approach to a larger number of already preselected compounds or binding poses. However, the controversial results in the literature 

The AMBER and CHARMM nonbonded terms are used as a scoring function in several docking programs. Protein terms are usually 

In the context of scoring, the van der Waals term of force fields is mainly responsible for penalizing docking solutions with steric overlap between receptor and ligand atoms. The term is often omitted when only the binding of experimentally determined complex structures is analyzed.  

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DG was primarily developed as a mathematical tool for obtaining spahal structures when pairwise distance information is given [118]. The DG method does not use any classical force fields. Thus, the conformational energy of a molecule is neglected and all 3D structures which are compatible with the distance restraints are presented. Nowadays, it is often used in the determination of 3D structures of small and medium-sized organic molecules. Gompared to force field-based methods, DG is a fast computational technique in order to scan the global conformational space. To get optimized structures, DG mostly has to be followed by various molecular dynamic simulation. 

Three main classes of fast scoring functions can be distinguished force field-based methods, empirical scoring functions, and knowledge-based methods. The following sections are dedicated to a separate discussion of each method. 

Force Field-Based Methods. An obvious idea to circumvent parameterization efforts for scoring is to use nonbonded energies of existing, well-established molecular mechanics force fields for the estimation of bind-... 

However, the free energy of binding is a state function so, in a strict physical sense, additivity is not allowed. These scoring functions at low computational cost are suitable for the calculation of an estimation of the binding free energy. Three main classes can be separated force field-based methods, empirical methods, and knowledge-based methods. 

Note that these steps are equivalent to the force field-based method, but the forces are derived quantum mechanically. Accordingly, one can carry out simulations in the ground or electronically excited states as well as account for chemical reactions. 

Both quantum mechanical and force field-based methods have been employed in the attempt to model hydrogen transfer reactions. In free-radical chemistry, by far the most significant hydrogen transfer process involves the reaction between a carbon-centered radical and a chain-carrying reagent such as tributyltin hydride... 

Although the presented results do not offer the possibility to predict antimalarial potency in a quantitative manner, this method apparently allows an efficient discrimination between active and inactive analogues. Moreover, it takes into account aspects of charge delocalization which are difficult to capture by means of force-field based methods such as CoMFA. In view of the time and cost involved in such calculations, however, the authors propose this computationally more sophisticated method as a second selection step which could best be used after having sorted out the more active from the less active candidates by a less expensive 3D-QSAR modelling technique [110]. 

Force field based methods also have merits. The main difficulties lie in their slowness, which hinders the search of a fragment s conformational space... 

Molecular dynamics simulations of biomolecules represent one of the most widely applied force field-based methods. They may be used to sample conformational space as required... 

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