MATCHING ALGORITHM(MC)
based on molecular shape map a ligand
DOCK, FLOG , LIBDOCK use MC for ligand
into an active site of a protein in terms of
matching
shape features and chemical information.
Incremental construction (IC)
put the ligand into an active site in a
fragmental and incremental fashion. The
ligand is divided into several fragments
DOCK 4.0, SLIDE USE THIS TECHNIQUE
by breaking its rotatable bonds and then
one of these ragments is selected to
dock into the active site first.
ALGORTITHMS
Multiple Copy Simultaneous Search
(MCSS) and
It makes fragment based approach for de
nova design of ligands.
LUDI
focuses on the hydrogen bonds and
hydrophobic contacts which could be
AUTODOCK EARLEIER VERSION, QXP AND
formed between the ligand and protein.
AFFINITY use Monte carlo technique
Monte Carlo
STOCHASTIC METHOD
generate poses of the ligand through
Search the conformational space by bond rotation,rigid-body translation or
randomly modifying a ligand rotation. The conformation obtained by
conformation or a population of ligands. this transformation is tested with an
GENETIC ALGORITHM energy- based selection criterion. If it
passes the criterion, it will be saved and
further modified to generate next
conformation.
Genetic algorithm
One of stochastic methods
stems from Darwin’s theory of evolution.
Degrees of freedom of the ligand are encoded as binary
strings called genes.
These genes make up the ‘chromosome’ which actually
represents the pose of the ligand.
Mutation and crossover are two kinds of genetic operators
in GA.
Mutation makes random changes to the genes;
crossover exchanges genes between two chromosomes.
When the genetic operators affect the genes, the result is
a new ligand structure.
New structures will be assessed by scoring function,
Genetic algorithms have been used in AutoDock , GOLD
and DARWIN
Scoring:
Scoring functions involve estimating the binding affinity between the protein and ligand and through these functions, adopting various assumptions
and simplifications.
It separates the correct poses from incorrect poses, or binders from inactive compounds in a reasonable computation time.
3 types of scoring functions: Scoring functions can be divided in force-field-based, empirical and knowledge-based scoring functions
o FF based scoring functions involves the calculation of binding energy by different non-covalent interactions. Softwares like Autodock use
this kind of scoring function
o Empirical involves different component for energy like hydrogen bonding, etc.,
o Knowledge based scoring function: Based on statistical data analysis.
DOCKING PROCEDURES:
Manual docking
Molecular modelling can be used to dock, or fi t, a molecule into a model of its binding site.
If the binding groups on the ligand and the binding site are known, they can be defined by the operator such that each binding group in the ligand
is paired with its complementary group in the binding site.
The ideal bonding distance for each potential interaction is then defined and the docking procedure is started.
The program then moves the molecule around within the binding site to try and get the best fi t as defined by the operator
Automatic docking
Softwares that automatically dock ligands into a binding site with the minimum of input from an operator.
an important application of automatic docking programs is to carry out virtual screening of hundreds of different molecules with the aim of
identifying new lead compounds that will interact with the target
The simplest approach to automatic docking is to treat the ligand and the macromolecular target as rigid bodies. Th is is acceptable if the active
conformation of the ligand is known or if the ligand is a rigid cyclic structure.
Rigid docking by shape complementarity
docking procedure is carried out purely in terms of steric complementarity
If the binding mode is acceptable, an optimization process is carried out which ‘fine tunes’ the position of the ligand in the binding site.
This minimizes unfavourable steric interactions and optimizes intermolecular interactions between the ligand and the binding site.
The binding energy of the ligand is now measured and a score is given for that binding mode.
