ANKITA A. SHUKLA

A REVIEW ON MOLECULAR MODELING

PRESENTED BY:

Ms. ANKITA A. SHUKLA

GUIDED BY: Mr.

M.K.MUNDE

ANKITA A. SHUKLA

MOLECULAR MODELING. WHY MODELING AND MOLECULAR

MODELING? WHY CHEMIST USE MODELS? IMPORTANT CHARACTERISTICS OF

MODELS.. MOLECULAR MODELING TOOLS.

MOLECULAR MODELING STRATEGIES.

MOLECULAR MODELING PROPERTIES.

MOLECULAR SIMULATION METHOD.

APPLICATIONS.

CONTENTS

ANKITA A. SHUKLA

Molecular modeling

encompasses all theoretical methods and

computational techniques

used to model or mimic the behaviour of

molecule.

Molecular model is

concerned with ways to describe the behaviour of

molecules and molecular system.

The common features of molecular modeling

techniques is the atomistic

level description of the molecular

system.

ANKITA A. SHUKLA

Modeling is a tool for doing chemistry. Models are central

for understanding of chemistry.

Molecular modeling is a discipline concerned

with developing models of molecular system , chemical reactions.

Models are some kind of representation of a

system, usually simplified, that allows for description

and prediction of properties of interest

Molecular modeling can be performed

by currently available software.

Why modeling and molecular modeling ?

ANKITA A. SHUKLA

A. Molecular modeling allows us to do and teach chemistry better by providing better tools for Investigating , Interpreting, Explaining, and Discovering new phenomena (for Drug)

B. Due to the advance in methodology and computer technology an alternative approach become feasible namely molecular simulation.

C. Fluids consist of molecules and their thermo physical properties are determined by the molecular interaction.

D. Molecular models describe these molecular interactions by means of parameterized potential function.

ANKITA A. SHUKLA

To help with analysis and interpretation of experimental data

To uncover new laws and formulate new theories To help solve problems and hint solutions before doing

experiments To help design new experiments To predict properties and quantities that is difficult or

even impossible to observe experimentally

Why chemists use models?

ANKITA A. SHUKLA

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:

ANKITA A. SHUKLA

The tools of the trade have gradually evolved from physical models and calculators, including the use of programmable calculators as visualization aids, computers running analysis pack- ages such as sylbyl and most recently integration using internet based tools and work benches in HTML, Java script, etc.

Molecular Modeling Tools

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HARDWARE

•Various classes of computers are required formolecular modeling.•For chemical information systems the choice of a computer is generally larger, and many packages run on VAX, IBM, or PRIME machines.

SOFTWARE

•The computational chemistry programmes allow scientists to generate and present molecular data including geometries, energies and properties.

Molecular Modeling Tools

ANKITA A. SHUKLA

Direct drug

design

Indirec

t drug

design

Molecular Modeling Strategies

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DIRECT DRUG

DESIGN

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.

ANKITA A. SHUKLA

INDIRECT DRUG DESIGN

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 design on the other ligand molecules that bind well to the site.

ANKITA A. SHUKLA

The first step to derive a new lead, also called secondary lead, will be to study the stereo electronic properties of the selected primary leads.

The next step is to find compounds which contain it embedded in their structure by three- dimension database searching.

Prerequisites for effective three-dimensional searching are large databases of three-dimensional structures and suitable software to perform this search.

When the lead is available then the next step is lead optimization

CADD Strategies in the Drug Discovery Process

ANKITA A. SHUKLA

Molecular mechanics

Dispersion and repulsion

Geometry

Electrostatics

Quantum mechanics

Molecular modeling properties

ANKITA A. SHUKLA

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

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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

ANKITA A. SHUKLA

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 by using GAMESS.

Geometry

ANKITA A. SHUKLA

Intermolecular electrostatics interactions are mainly occur due to static polarities of single molecules that can well be obtained by quantum chemistry.

Electrostatics

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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.

Dispersion and repulsion

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Molecular simulation

method

Molecular dynamics

Periodic boundary condition

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Molecular dynamics

Molecular dynamics is an approach to mimic the

movement of molecule in an ensemble.

Periodic boundary condition

By applying PBC the amount of interaction partners of a molecule in a simulation

theoretically rises to infinity

ANKITA A. SHUKLA

Applications

1 •Generation of Chemical Structures

2 •Molecular Structure Visualization

3 •Modeling of Drug Receptor Interactions

ANKITA A. SHUKLA

THANK YOU