04/11/23

04/11/23

Computational Aided Drug designingGroup Members Ayesha Aftab MalikZahra HanifKhadija Ijaz

Department of Bioinformatics and Technology International Islamic University Islamabad

Drug A chemical substance that affects the

processes of the mind or body which is used in

diagnosis

Treatment

prevention

of disease or other abnormal condition.

DRUG DESIGN

Drug design, is the inventive process of finding new medications based on the knowledge of a biological target.

Drug designing…..

Selected/designed molecule should be:

organic small molecule. complementary in

shape to the target. Oppositely charge to

the biomolecular target .

Drug designing…..

This molecule will: interact with target bind to the target activates or inhibits the function of a

biomolecule such as a protein

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Cont……..• Drug design frequently but not

necessarily relies on computer modeling techniques.

Types of drug design

1. Ligand based drug design

2. Structure based drug design

Ligand based drug design

• Ligand-based drug design relies on knowledge of other molecules that bind to the biological target of interest

• used to derive a pharmacophore

Structure based drug design

Structure-based drug design relies on knowledge of the three dimensional structure of the biological target obtained through methods such as

x-ray crystallography NMR spectroscopy.homology modeling

Structure based drug design…..

• Using the structure of the biological target, drugs that are predicted to bind with to the target may be designed using interactive graphics the intuition of a medicinal chemist.automated computational procedures

Techniques of drug design

X-ray crystallography

starting point for gathering information from mechanistic drug design.

determine structural information about a molecule.

provides the critically important coordinates needed for the handling of data by computer modeling system.

NuclearMagnetic Resonance (NMR)

NMR uses much softer radiation

examine molecules in the more mobile liquid phase

three-dimensional information will be obtained.

examine small molecule-macromolecule complexes, such as an enzyme inhibitor in the active site of the enzyme.

HOMOLOGY MODELING:

Homology modeling, also known as comparative modeling of protein, refers to constructing an atomic-resolution model of the "target" and an experimental three-dimensional structure of a related homologous protein (the "template").

Computer Aided Drug design(CADD)

Computer Aided Drug design• CADD represents computational

methods and resources that are used to facilitate the design and discovery of new therapeutic solutions.

History of Drug development

Screening for new drugs

Plants or Natural Product Plant and Natural products were source for medical

substance Example: foxglove used to treat heart failure

Accidental Observations Penicillin is one good example Alexander Fleming observed the effect of mold.

Modifications for improvement

• Modifications to improve performance are often carried out using chemical or bio fermentative means to make changes in the lead structure or its intermediates.

• for some natural products, the gene itself may be engineered so that the producer organism synthesizes the modified compound directly.

Mechanism based drug design

• When the disease process is understood at the molecular level and the target molecule(s) are defined, drugs can be designed specifically to interact with the target molecule in such a way as to disrupt the disease.

Basic Mechanism of CADD

1. Selection of disease

• The first step in the design of drugs to treat diseases is to determine the biochemical basis of the disease process.

• Ideally, one would know the various steps involved in the

physiological pathway that carries out the normal function. In

addition, one would know the exact step(s) in the pathway

that are altered in the diseased state.

• Knowledge about the regulation of the pathway is also

important. Finally, one would know the three- dimensional

structures of the molecules involved in the process.

Target selection

• There are potentially many ways in which biochemical

pathways could become abnormal and result in disease.

• Therefore, knowledge of the molecular basis of the disease is

important in order to select a target at which to disrupt the

process.

Target selection

Categories of targets:Target for mechanistic drug design

usually fall into three: enzymes, receptors nucleic acids.

STRUTURE DETERMINATION• Crystal structure of target protein can

be taken from PDB database

PDB database

Determination of active site of target protein Only a small part of a lead compounds

may be involved in the appropriate interaction. The relevant groups on a molecule that interact with the receptor and are responsible for activity are collectively known as pharmacophore.

Selection of ligands/drugs

Molecular docking

• Docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex.

• Flexible docking programs like DOCK, AutoDock and Molecular Operating Environment (MOE) enable user to predict favorable biological target–ligand complex structures with reasonable accuracy and speed.

AutoDock AutoDock is a suite of automated

docking tools. It is designed to predict how small molecules, such as substrates or drug candidates, bind to a receptor of known 3D structure.

Visualization of docked complex

The docked complex is then visualized and studied using a software like VMD (Visual Molecular Dynamics).

VMD

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Retrieving 3D structures• first step for protein visualization is to extract the protein

structure from a structure database in specific file formats like PDB format or Cn3D format,which would serve as input for the 3D visualization programs.

Retrieving from PDB database• protein data bank(PDB)• -http://www.rcsb.org/pdb/home/home.do

Retrieving from PDB database

What isVMD?

• VMD (Visual Molecular Dynamics) is a molecular visualization program for displaying,

• animating, and analyzing large biomolecular systems such as proteins, nucleic acids, lipid bilayer

• assemblies, etc. using 3-D graphics and built-in scripting. VMD supports computers running

• MacOS X, Unix, or Windows, is distributed free of charge, and includes source code. It may be

• used to view more general molecules, as VMD can read standard Protein Data Bank (PDB) files

• and display the contained structure. VMD provides a wide variety of methods for rendering and

• coloring a molecule. VMD can be used to animate and analyze the trajectory of a molecular

• dynamics (MD) simulation. In particular, VMD can act as a graphical front end for an external

• MD program by displaying and animating a molecule undergoing simulationon a remote

• computer.

Key Features of VMD• General 3-D molecular visualization with extensive drawing and coloring methods

• Extensive atom selection syntax for choosing subsets of atoms for display

• Visualization of dynamic molecular data

• Visualization of volumetric data

• Supports all major molecular data file formats

• No limits on the number of molecules or trajectory frames, except available memory

• Molecular analysis commands

• Rendering high-resolution, publication-quality molecule images

• Movie making capability

• Building and preparing systems for molecular dynamics simulations

• Interactive molecular dynamics simulations

• Extensions to the Tcl/Python scripting languages

• Extensible source code written in C and C++

BENEFITS OF CADD

DRUG DISCOVERY:Use of computing power to streamline drug discovery and development process.

Elimination of compounds with undesirable propertiesDesign of in silico filters to eliminate

compounds with undesirable properties (poor activity and/or poor Absorption

Distribution, Metabolism, Excretion and Toxicity, ADMET) and select the most promising candidates

Identify and optimize new drugs Leverage of chemical and biological

information about ligands and/or targets to identify and optimize new drugs

Benefits• TIME SAVING: The process of drug discovery and

development is a long and difficult one, and the costs of developing are increasing rapidly. Today it takes appropriately 10years and $100million to bring a new drug to market.

REDUCED COST: The use of new computer-based drug

design techniques has the ability to accomplish both of these goals and to improve the efficiency of the process as well, thus reducing costs.

• IMPROVE QUALITY OF LIFE:

The emphasis now is not just on finding new ways to treat human disease, but also on improving the quality of life of people in general.