Essentials of Computational Chemistry

2.6 FORCE FIELDS AND DOCKING 63
Figure 2.10 Docking grid constructed around a target protein. Each gridpoint can be assigned a force
field interaction potential for use in evaluating binding affinities. Note that this grid is very coarse to
improve viewing clarity; an actual grid might be considerably finer.
modeled by Eqs. (2.16) and (2.22). Moreover, to further simplify matters, one may consider
the rigid enzyme to be surrounded by a three-dimensional grid, as illustrated in Figure 2.10.
Given a fixed geometry, one may compute the interaction potential at each grid point for
a molecular mechanics atom having unit values of charge and Lennard-Jones parameters.
Then, to compute interaction energies, one places a proto-drug molecule at some arbitrary
position in space, and assigns each atom to be associated with the grid point nearest it (or
one could interpolate if one were willing to pay the computational cost). The potential for
each point is then multiplied by the appropriate atomic parameters, and the sum of all atomic
interactions defines the docking energy for that particular position and orientation. After a
suitable number of random or directed choices of position have been surveyed, the lowest
docking energy is recorded, and one moves on to the next molecule in the test set.
Of course, this analysis is rather crude, since it ignores a number of physical phenomena
in computing an interaction energy. For instance, we failed to account for the desolvation
of the enzyme and the substrate along the surfaces over which they come into contact, and
we did not consider the entropy loss associated with binding. As such, the goal of most
docking studies tends to be to provide a simple filter that can narrow a vast database down
to a merely large database, to which more refined techniques may be applied so as to further
winnow down possible leads.