Computational Drug Discovery and Design

The most energetically favorable positions based on the visual

inspection of GRID-calculated isosurfaces are used to place

water molecules (Fig.1c and d;seeNote 5).

6. Another GRID run should be carried out on the same initial
   receptor structure using the carbon sp^3 probe as an approxima-
   tion to account for solvent exclusion upon ligand binding
   (Fig.1e).


7. After overlapping the obtained isosurfaces for the carbon sp^3
   probe with the predicted water molecules, the water molecules
   within 1.5 A ̊to the minima of the carbon sp^3 energy grid are
   discarded (Fig.1f;seeNote 6).


8. The receptor structure together with the de novo placed water
   molecules can be used for molecular docking experiments (see
   Note 7).

2.2 Dynamic
Molecular Docking
(DMD): Targeted
MD-Based Docking
Approach Accounting
for Explicit Solvent and
the Complete
Flexibility of Receptor
and Ligand

This method exploits an MD approach to perform a local molecular

docking experiment (seeNote 8). In the first step, the ligand, which

is placed at a certain distance from the receptor, is moved slowly

toward a putative binding site on the surface of the receptor as a

consequence of the application of an additional harmonic potential

(Fig.2). In the second step, an MD simulation of the complex

obtained in the first step is carried out without additional poten-

tials. During both steps, the system is solvated explicitly, therefore,

accounting for solvent-mediated interactions. DMD runs are

repeated to obtain a statistical ensemble of docking solutions.

Fig. 2Schematic representation of DMD procedure from Method II: (a) Receptor

(in cartoon) and ligand (in stick representation) are at the initial distance,t¼0;

(b) Docked complex after the targeted MD step,t¼ttMD.C,F, andLpoints are

core, focus, and ligand center atoms

448 Sergey A. Samsonov