2. Different term used in in silico design
Receptor/Host/Lock- receiving molecules (protein)- large.
Ligand/Guest/key- molecule bind to receptor- small.
Docking-In the field of molecular modeling, docking is a method which
predicts the preferred orientation of one molecule to a second when a ligand
and a target are bound to each other to form a stable complex.
Binding mode- conformation of ligand receptor bound to each other.
Scoring- evaluating a particular pose by counting the number of favourable
intermolecular interaction.
3. Ranking- classify ligands most likely to interact favourably to a particular
relation based on G of binding.
Hit-ligand with high rank.
Lead- hit with biological activity.
Pharmacophore- special arrangement of atoms or groups believed to be
responsible for biological activity.
Rational drug design- Modulatioin of specific biological target may have
therapeutic value.
QSAR- Study ds. of physio chemical properties of a compound with its
biological/pharmacological activity.
Drug design – design of ligands.
4. Aim of molecular docking is to achieve an optimized conformation and
relative orientation between protein ligand such that G is minimized.
IT is to study . . . .
Whether the two molecules interact with each other.
If so what is the orientation that maximizes the interaction which minimizing
the total energy of the
complex
. GOAL…
Given a protein structure and predict its ligand bindings.
5. TYPE OF DOCKING
Rigid docking (lock and key)- In rigid, docking the
internal geometry of both the receptor and ligand are
treated as rigid.
Flexible Docking ( Induced fit)- An enumeration on
the rotation of one of the molecules (usually) is
performed. Every rotation the energy is calculated,
later the most optimum pose id selected.
9. Energy minimization
Whichever software program is used to create a 3D structure, a
process called energy minimization should be carried out once the
structure is built.
This is because the construction process may have resulted in
unfavorable bond lengths, bonds angles or torsion angles.
The energy minimization process is usually carried out by a molecules
mechanics program which calculates the energy of starting molecules ,
then varies the bond lengths ,and torsion angles to create a new
structure .
The energy of new structure is calculated to see whether it is
energetically more stable or not.
10. If the starting structure is inherently unstable ,a slight alteration in bond angle
or bond length will have a large effect on the overall energy of the molecules
resulting in a large energy difference (ΔE; Fig .1 ).
The program will recognize this and carried out
more changes , recognizing those which lead to
stabilization and those which do not.
Eventually a structure will be found where
structural variation result in only slight changes in
energy- an energy minimum.
11.
12. ENERGY MINIMIZATION
In short, it is a procedure that attempts to minimize the potential energy
of the system to the possible point.
The system makes several changes in the atom position through
rotation and calculates energy in every position.This process is
repeated many times to find the position with lowest energy until an
overall minimum energy is attained.
The one full round of an atom rotation is called minimization step or
iteration.
15. MINIMIZATION is to find a set of coordinates representing the minimum
energy conformation for the given structure.
Various algorithms have been formulated by varying the use of derivatives.
Three common algorithms used for this optimization :-
1) Steepest descent method
2) Conjugate gradient method
3) Newton-Raphson method
Other method:- 1) Downhill simplex method
16.
17.
18. B. Newton- Raphson minimization method
In this method , inverse of the second derivative matrix ( Hessian) is
used.
The method is the most computationally expensive per step of all the
methods utilized to perform EM.
First derivatives provide gradiant information while second derivative
furnish detail about the curvature of the function.
19.
20. HERE
Xn is the current x value
F(Xn) represents the value of the function at Xn
F’(Xn) is the derivative (slope) at Xn
Xn+1 represent the next x-value that you are trying to
find.
21. Conjugate Gradient method is an iterative gradient descent algorithm
for finding the minimum value of a function.
It’s most relevant application in energy minimization since it rapidly
solves large system of linear equation with an unknown minimum.
C.(Conjugate gradient method)
22. D. Quasi – newton Raphson method
These methods avoid the difficult evaluation of the generalized
inverse of the Hessian matrix.
Consequently , this methods are faster ones.
DFP ( Davidson, Fletcher and Powell) and BFGS
(Broyden,Fletcher,Goldfard and Shanno) methods are
representatives of this class.
23. Downhill Simplex method
It is a robust and non – derivative based method which
probably is one of the easiest method to implement.
The simplex methods , is a general mathematical solution
technique for solving linear programming problems.
The modal is put into the form of table , and then a number of
mathematically steps are performed on the table.
24. WHAT IS BIOACTIVE CONFORATION
It is a conformation a molecule must adopt to
be recognized by a receptor and produce a
biological response .
Predicting that conformations for flexible
small molecules is a challenging question in
drug design.
WHAT IS BIOACTIVE CONFORMATION
