Current State-of-the-art for Virtual Screening and Docking Methods - New Developments in Medicinal Chemistry - page 53

means of Molecular Dynamics simulations. It uses the semi empirical PM6
protocol coupled with the COnductor-like Screening MOdel solvation model
followed by density functional theory (DFT) calculations. The DFT-D3 dispersion
energy correction is included for the most stable conformers. The calculated
structures and free energies are in agreement with those of the experimentally
detected molybdocene-cysteine adducts [594].
The inability to quickly generate rapid/accurate/robust parameters for novel
chemical matter limits the application of molecular dynamics simulations in drug
discovery. It was recently reported the Force Field Toolkit (ffTK), which
minimizes common barriers to ligand parameterization. The protocol uses
algorithm and method development. It also uses automation of tasks. The
procedure can generate quantum mechanical target data, setup multidimensional
optimization routines and analyze parameter performance. Parameters are
developed for a small test set of molecules in order to reproduce experimentally
measured values for pure solvent properties and free energies of solvation [595].
Recent work reported free energy molecular dynamics simulations of stabilization
of duplex DNA and RNA. Umbrella sampling free energy simulations of dangling
cytosine and guanine nucleotides have been used to investigate the molecular
origin of dangling end effects. Calculated free energy contributions associated
with the presence of dangling nucleotides were in reasonable agreement with
experiment predicting the general trend of a more stabilizing effect of purine vs .
pyrimidine dangling ends. Both electrostatic and van der Waals interactions
contribute to the duplex stabilizing effect of dangling end nucleotides. The free
energy simulation scheme could also be used to design enhanced duplex
stabilization [596].
QUANTUM MECHANICS/MOLECULAR MECHANICS METHOD'S
Semi-classical statistical mechanics and empirical or ab initio derived force fields
can be used by atomistic methods to determine transport and thermodynamics
properties. For large systems, molecular mechanics can be used. The force fields
results from the fact that the total potential energy is differentiable with respect to