Molecular modelling-Needs and charcteristics

The term “ Molecular modeling “expanded over the last decades from a tool to visualize three-dimensional structures and to simulate , predict and analyze the properties and the behavior of the molecules on an atomic level to data mining.

1. Molecular modelling or more generally computational chemistry is the
scientific field of simulation of molecular systems.
Molecular modeling encompasses all theoretical methods and
computational techniques used to model or mimic the behavior of molecule.
The common features of molecular modeling techniques is the atomistic
level description of the molecular system.
Molecular modelling allow scientists to use computers to visualize
molecules by representing molecular structures numerically and simulating
their behavior with the equations of quantum and classical physics, to
discover new lead compounds for drugs or to refine existing drugs in silico.
The term “ Molecular modeling “expanded over the last decades from a tool
to visualize three-dimensional structures and to simulate , predict and
analyze the properties and the behavior of the molecules on an atomic level
to data mining.
1
Introduction

2. It is the platform to organize many compounds and their
properties into database and to perform virtual drug screening
via 3D database screening for novel drug compounds .
Basically in the computational chemistry , the free energy of
the system can be used to assess many interesting aspects of
the system.
In the drug design , the free energy may be used to assess
whether a modification to a drug increase or decrease target
binding.
The energy of the system is a function of the type and number
of atoms and their positions.
Molecular modelling softwares are designed to calculate this
efficiently.
2

3. Why modeling and molecular modeling ?
Modeling is a tool for doing chemistry. Models are central for
understanding of chemistry.
Models are some kind of representation of a system, usually simplified,
that allows for description and prediction of properties of interest.
Molecular modeling allows us to do and learn chemistry better by
providing better tools for Investigating , Interpreting, Explaining, and
Discovering new phenomena (for Drug).
Molecular modeling is a discipline concerned with developing models of
molecular system, chemical reactions.
Molecular models describe the molecular interactions by means of
parameterized potential function.
Molecular modeling can be performed by currently available software.

4. Need of Models

5. a)Level of simplification:very simple to very
complex .
b)Generality: general or specific, i.e. relate only to
specific systems or problems.
c)Limitations:one must always be aware of the range
of applicability and limits of accuracy of any
model.
d)Cost and efficiency:CPU time, memory, disk space.
 
Important characteristics of models are:

6. Quantum mechanics Molecular mechanics
Ab initio methods DFT method Semi-empirical methods
Molecular Modelling
Molecular modeling properties
Molecular mechanics
Quantum mechanics
Geometry
Electrostatics
Dispersion and repulsion

8. In the direct approach, the three dimensional features of the
known receptor site are determined from X-ray
crystallography to design a lead molecule.
In direct design the receptor site geometry is known; the
problem is to find a molecule that satisfies some geometry
constraints is also a good chemical match.
After finding good candidates according to these criteria a
docking step with energy minimization can be used to predict
binding strength.
Direct drug design
Molecular Modeling Strategies

9. The indirect drug design approach involves comparative
analysis of structural features of known active and inactive
molecules that are complementary with a hypothetical
receptor site.
If the site geometry is not known, as is often the case, the
designer must base the design on other ligand molecules that
bind well to the site.
Indirect drug design

10. The process of finding the minimum of an empirical potential energy
function is called as the Molecular mechanics(MM).
The process produce a molecule of idealized geometry.
Molecular mechanics describes the energy of a molecule in terms of a
simple function which accounts for distortion from “ideal” bond distances
and angles, as well as and for nonbonded van der Waals and Coulombic
interactions.
Molecular mechanics is a mathematical formalism which attempts to
reproduce molecular geometries, energies and other features by adjusting
bond lengths, bond angles and torsion angles to equilibrium values that are
dependent on the hybridization of an atom and its bonding scheme.
Molecular mechanics

11. •Molecular mechanics breaks down pair wise interaction into
Bonded interaction ( internal coordination )
- Atoms that are connected via one to three bonds
Non bonded interaction
- Electrostatic and Van der waals component
The general form of the force field equation is
E
P (X) = E
bonded + E
nonbonded

12. •Bonded interactions
•Used to better approximate the interaction of the adjacent atoms.
•Calculations in the molecular mechanics is similar to the Newtonians law
of classical mechanics and it will calculate geometry as a function of steric
energy.
E
bonded = E
bond +
E
angle +
E
dihedral
Bond term
E
bond = ½ k
b (b – b
o)
2
Angle term
E
Angle
= ½ k
θ
(θ – θ
0
)
Energy of the dihedral angles
E
dihedral = ½ k
Φ(1 – cos (nΦ + δ)

13. • Non bonded interaction
• Nearly applied to all pairs of atoms.
•The nonbonded interaction terms usually include electrostatic
interactions and van der waals interaction, which are expressed as
coloumbic interaction as well as Lennard-Jones type potentials,
respectively.
•All of them are a function of the distance between atom pairs ,r
ij .
•E
Nonbonded = E
van der waals +
E
electrostatic
•E
van der waals –weak intermolecular forces between molecules or atomic groups
•E
electrostatic- attraction or repulsion of different particles and materials based on their electrical
charges.


Lennard Jones potential
Coulomb's Law

14. H
C
C
H
H
Graphical representation of the bonded and non bonded interaction and
the corresponding energy terms.
E
coulomb
Electrostatic attraction
E
vdw
Van der waals
Y
ij
θ
0
K

θ
K
b
K
Ф
E
Ф

Ф
0
E

θ
E
b
b
0
b
Bond stretching
Dihedral rotation
Angle bending

15. Quantum mechanics
In this process, properties of the molecules are calculated
by equations of quantum physics involving interactions
between electron and nuclei.
Electron movements are more rapid and since they rotate
independently of the nucleus, it is possible to describe
electronic energy separately from the nuclear one.
Quantum mechanics is basically the molecular orbital
calculation and offers the most detailed description of a
molecule’s chemical behavior.
HOMO – highest energy occupied molecular orbital
LUMO – lowest energy unoccupied molecular orbital

16. Quantum methods utilize the principles of particle physics
to examine structure as a function of electron distribution.
Geometries and properties for transition state and excited
state can only be calculated with Quantum mechanics.
Their use can be extended to the analysis of molecules as
yet unsynthesized and chemical species which are difficult
(or impossible) to isolate.

17. •Quantum mechanics is based on Schrödinger equation
HΨ = EΨ = (U + K ) Ψ
E = energy of the system relative to one in which all atomic
particles are separated to infinite distances
H = Hamiltonian for the system .
It is an “operator” ,a mathematical construct that operates
on the molecular orbital , Ψ ,to determine the energy.
U = potential energy
K = kinetic energy
Ψ = wave function describes the electron distribution around
the molecule.

18. Geometry
All geometric data of the molecular models, i.e. bond length, angles and
dihedrals, were determined based on calculations.
Therefore, a geometry optimization, i.e. an energy minimization was initially
performed for all molecules.
Electrostatics
Intermolecular electrostatics interactions are mainly occur due to static
polarities of single molecules that can well be obtained by quantum chemistry.
Dispersion and repulsion
For an estimation of dispersive and repulsive interaction at least two
molecules must be taken into account.
The dispersive and repulsive interactions are usually only a very small
fraction of the total energy calculated by QC highly accurate method like
coupled cluster with large basis sets or even extrapolations to the basis set
limit must be used for this task.

19. Target
Identification
&Validation
Hit
Identification
Lead
Identification
Lead
Optimisa-
tion
CD
Prenomi-
nation
Concept
Testing
Development
for launch
Launch
Phase
FDA Submission
Launch
Finding Potential
Drug Targets
Validating Therapeutic Targets
Finding Potential Drugs
Drug<>Target<>Therapeutic Effect
Association Finalized
Testing in Man
(toxicity and efficacy)

21. Receptor
Ligand
U
n
k
n
o
w
n
K
n
o
w
n
Unknown Known
Generate 3D structures,
HTS, Comb. Chem
Build the lock and then
find the key
Molecular
Docking
Drug receptor
interaction
2D/3D QSAR and
Pharmacophore
Infer the lock by
expecting key
De NOVO Design ,
Virtual screening
Build or find the key
that fits the lock
Receptor based drug design
Rational drug design
Indirect drug design
Homology modelling
Basic Modelling Strategies