DOCKING TECHNIQUES

Methodologies for Docking: There are several well-defined and generalized methodologies
for docking, namely:
(i) Interactive graphics,
(ii) Docking by superimposition,
(iii) Energy-based docking programmes,
(iv) Builders, growers, and linkers,
(v) Flexible docking, and
(vi) Fragmentation approach.
These different aspects related to methodologies for docking shall now be treated
individually in the sections that follow:

A. Interactive Graphics: The interactive graphics represent the most common as well as
the simplest method for docking. The other end of complexicity essentially makes use of the
rather complete free-energy perturbation thereby embracing the acceptable molecular
dynamics method. Of these two ensuing extreme methods there exist a good number of such
ligands that exclusively utilizes the most sophisticated automated methodologies.

Examples:
(a) For analyzing the crystal structure of a target-drug molecule, and
(b) For docking of a ligand at the active site.
In general, these methods do require prominently the wisdom, skill, and above all the much
desired intuition inherited by a medicinal chemist to solve many intricate problems invariably
encountered, of course, with the help of ever-expanding horizons of computational technique.
However, these methodologies are not only giving rise to purely qualitative results, but also
are time-consuming and labour-intensive nature.

B. Docking by Superimposition: It has been established beyond any reasonable doubt that
one may, with great ease and convenience, superimpose an altogether new ligand derived
meticulously from the 3D coordinate structures of the available ligand-bound protein upon
the prevailing ligand. This may be considered as the ab initio position. In this manner one
may skilfully utilize the specific grid based energy programmes so as to determine the
precise scores having different ligands.

Example: Holtz and Folkers** Exemplified the typical case of a major histocompatibility
complex (MHC) peptide as depicted in Figures : 6. It broadly and vividly shows the
simplified model of binding of a nonapeptide i.e., having nine peptide linkages, to a Class I
MHC-peptide as illustrated in HLA-B27.

C. Energy-Based Docking Programs: There are quite a few well-known docking

programmes, as discussed earlier, that essentially make use of a particular ‘energy-grid’
with an assumption that body ligand and target-molecule happen to be absolutely ‘rigid’ in
nature. Importantly, the energy based docking programmes may afford two important
functionalities to the ‘ligand’, namely: (a) conformational flexibility; and (b) motional
flexibility.
Examples:
(i) DOCK 3.5: Kuntz et al.* (1982) introduced a highly promising and effective means for
the 3D database search. In fact, there exist quite a few well-known modelling packages
viz., CHEM,
HYPERCHEM, LIGAND, MOE etc. that essentially provide a plethora of such elaborated
programmes to perform specifically the energy-grid based docking.

Applications: The various applications of DOCK 3.5 are as follows:

(1) Capable of taking up only one ligand at a time.
(2) Prime aim is to lay hand upon the starting model of the proposed ligand-receptor
complex that could be further modified and refined based on need and wisdom.
(3) Ligand may be taken on as ‘rigid’ as well as ‘flexible’.
(4) Success rate of such studies is solely dependent upon the inputs provided by the various
physicochemical studies.
(ii) MHC-Peptide: Holtz and Folkers** (1996) put forward the particular coordinate system
whereby the Z-axis is duly projected along the length of the active-site cleft. In this instance,
the different observable and registered translations all along the Z-axis, together with the
rotations around the Z-axis are recorded duly over the full-range, but with various step sizes
ranging between 3Å to 30Å. However, the native ligands of MHC are peptides.

Example: An actual study using CoMFA and eight selected peptides related to the helical
superimposition segment was performed meticulously. A chain of six specific amino acids
i.e., Gly-Ile-Leu-Phe-Thr-Leu was carefully docked by a manual process right inside the
peptide-binding zone strategically located in the binding-pocket of MHC peptide. To
achieve this objective the electron density map was employed that critically maintained the
volume under control so that the ‘ligand’ should fit into it perfectly. The first residue, n-
terminal of glycine, shall duly fit in at a H-bonding distance with respect to the conserved
residues like: Tyr 7, Tyr 59, and Tyr 171 as illustrated in Figure: 6. The second residue,
isoleucine, has been proved to be one of the previously detected and anchored residues
kept under protection from the corresponding peptide ligand. In Figure: 6 the six binding
pockets are distinctly
labeled from A to F.
D. Builders, Growers, and Linkers: In a broader sense, the 3D database searching
methods
are obviously more precise and appropriate in comparison to several other techniques due to
the fact that
the existing overall available perceptive knowledge of receptor-ligand recognition is still
not absolutely
clear and perfect.
Alternatively, one may initially determine the most probable exact location wherein the
moieties
under investigation are adequately predicted by strategically establishing the precise position
of the Hbonding
sites e.g., in LUDI or multiple-bonding sites e.g., in HOOK, and ultimately linking them
with the best-fitting fragments from the database libraries.
E. Flexible Docking : Flexible docking usually refers to a not-so-rigid kind of virtual
screening
durg design technology so as to evaluate specifically the binding of ligands to the
macromolecular targets.
In other words, it permits limited conformational flexibility amongst the target and ligand
molecules.
It is, however, pertinent to state here that this type of suggestive action mode is proved to be
quite good and effective for peptide docking, but it may turn out to be fairly expensive
proposition. Therefore, it is always advisable and wise to pre-screen the proposed ligand
flexibility in particular.

F. Fragmentation Approach: In actual practice, the fragmentation approach affords rather

complete flexibility to the ligand; and subsequently, binds them at the appropriate target site.
Example: CAVEAT* serves as a befitting example of this fragmentation approach.
Following are a few vital and important Docking Programmes commonly used in the design
of newer drug molecules: