Chemistry Reference
In-Depth Information
whereas the permanent fluctuations in the electron distribution of one molecular entity can induce a temporary
dipole in the neighboring molecule [18].
Molecular Interaction Fields (MIFs) are appropriate tools for investigating the energetic conditions between a drug
target and a ligand and to help in understanding the interaction forces in the complexes. A MIF describes the
variation of the interaction energy between a 3D molecular structure and a specific chemical probe. The 3D
molecular structure can be represented by a protein drug receptor, an enzyme, a DNA polymer, an organic
compound,
etc.
The chemical probe represents an atom or a small group of atoms (molecular fragment). The
objective is to predict where ligands can bind to a biological target and understand the factors that interfere with
binding in order to design ligands with improved biological activity [19,20]. The MIF theory is extensively applied
in drug discovery projects, including structure-based drug design, QSAR and prediction of pharmacokinetic
properties of ligands.
MOLECULAR INTERACTION FIELDS THEORY
Goodford [20] described a method to assess the fit of ligands within the active site of its molecular target by
determining energetically favorable binding sites on biologically important macromolecules. The pioneer
computational method was able to display energy contour surfaces in three dimensions in phase with the
macromolecular chemical structure representation, leading in this way to the design of ligands considering
simultaneously energy and shape.
The calculation of MIFs can translate the ability of a giving molecule to interact with others. The interaction of a
molecule with a chemical probe, which represents any kind of functional group, located at any x, y, z coordinate
around the molecule is the basic idea behind the MIF concept. Computing the measurement of this interaction at
sample positions, a giving set of energy values are obtained and can be displayed graphically as energy contours.
These contours represent specific areas in space where molecules holding a probe-like group could perform
energetically favorable interactions, describing the potential of two molecules approaching each other to interact [18].
The calculations of MIFs for an attractive drug target structure can lead to identification of relevant regions of the
biomacromolecule where potential ligands could establish intermolecular interactions. This is particularly important
to guide the design and evaluation of potent and selective ligands. In the same way, the MIFs can be computed for a
group of known ligands, without the prior knowledge of the drug receptor structure, in order to help the
discrimination of the molecular characteristics, regarding the ability to establish interactions, which are important to
maintain or improve biological activity. [21]
When performing calculations a regular array of GRID nodes are established throughout and around the molecular
structure. In this way, a potential energy function is calculated for a specific chemical probe located at the first point
of the GRID. Successive probe positions are sampled until the potential energy is computed for each GRID node
(Fig.
1
). Considering a drug target macromolecule, the dimensions of the array are determined so that the first GRID
node is positioned outside the protein structure leading to small energy values. Nevertheless, some subsequent points
can intersect the macromolecule leading to large positive energies. The points which are located in the proteins
interatomic spaces allow the determination of favorable ligand interaction sites where negative interaction energies
are assigned [20]. These favorable regions represent promising locations where a ligand can place a functional group
similar to the probe. When computed for a ligand molecule, these represent potential groups of the drug target
binding site where noncovalent bonding interactions could be established [21].
The energy function used to compute the nonbonded interactions of the chemical probe with the molecule studied in
a given node is composed, basically, of a sum of the Lennard-Jones and electrostatic functions. The Lennard-Jones
function is used to explain the attractive van der Waals force by a combination of the dispersion and repulsion
energies in order to detect the zone of mutual attraction between nonbonded atom pair interactions.
Considering Equation 1 and the calculation of van der Waals energy, r
ij
represents the distance between a pair of
nonbonded atoms. A
ij
and C
ij
are parameters representing the repulsion term and the attraction term, respectively.
