computer aided drug designing and molecular modelling

Computer-Aided Drug Designing $ Molecular

modellingPresented by

NEHLA YAHCOOBDept: pharmaceutical chemistry

Grace college of pharmacy

Contents History Life cycle of drug discovery

› Traditional› CADD

Introduction to CADD Objectives of CADD Priciples involoved in CADD Softwares for CADD

History of Drug Discovery Early 19th century - extraction of compounds from plants

(morphine, cocaine).

Late 19th century - fewer natural products used, more synthetic substances. Dye and chemical companies start research labs and discover medical applications.

1905 - John Langley: “The concept of specific receptors”

1909 - First rational drug design.

Goal: safer syphilis treatment than Atoxyl.Paul Erhlich and Sacachiro Hata.Synthetic: 600 compounds; evaluated ratio of

minimum curative dose and maximum tolerated dose. They found Salvarsan (which was replaced by penicillin in the 1940’s)

1960 - First successful attempt to relate chemical structure to biological action quantitatively.

As As

OH

NH2

OH

NH2

Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to influence a drug’s activity, stability, etc.

Life Cylce of Drug Design

Traditional Life Cycle

Synthetic or Natural Compounds

Preclinical Trails

Clinical Trails

Modern drug design

Target Selection Lead Identification Lead Optimization

Identification of Potential

Target

Target Verification

Target Selection

Screen Development

High Throughput Screening

Secondary Assay/MOA

Lead Explosion

Potency in Disease

Pharmacokintetics

Drug Discovery & DevelopmentIdentify disease

Isolate proteininvolved in disease (2-5 years)

Find a drug effectiveagainst disease protein(2-5 years)

Preclinical testing(1-3 years)

Formulation &Scale-up

Human clinical trials(2-10 years)

FDA approval(2-3 years)

File

IN

D

File

NDA

Identify disease

Isolate protein

Find drug

Preclinical testing

GENOMICS, PROTEOMICS & BIOPHARM.

HIGH THROUGHPUT SCREENING

MOLECULAR MODELING

VIRTUAL SCREENING

COMBINATORIAL CHEMISTRY

IN-VITRO & IN-SILICO ADME MODELS

Potentially producing many more targetsand “personalized” targets

Screening up to 100,000 compounds aday for activity against a target protein

Using a computer topredict activity

Rapidly producing vast numbersof compounds

Computer graphics & models help improve activity

Tissue and computer models begin to replace animal testing

Computer-Aided Drug Designing (CADD)

oComputer-Aided Drug Designing (CADD) is a specialized discipline that uses computational methods to simulate drug-receptor interactions

oCADD methods are heavily dependent on bioinformatics tools, applications and databases

CADD (Approaches) :

Strucuture Based

Crystal Strucuture Analysis

Homolgy Modeling

Computional Analysis of Protien Lignad Interaction

Modification of Ligand within the Active Site for Better Design

Ligand Based

QSAR Lead Identification

In-Silico solubility, BBB & Toxicity Prediction

Lead Optimization

Preclinical Trail

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 and platform to organize many compounds and their properties into database and to perform virtual drug screening via 3D database screening for novel drug compounds .

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Principles Governing CADD

Molecular Mechanics Quantum Mechanics

Molecular mechanics

Molecular mechanics refers to the use of classical mechanics to model the geometry and motions of molecules.

Molecular mechanics methods are based on the following principles: 1) Nuclei and electrons are lumped into atom-like particles. 2) Atom-like particles are spherical and have a net charge. 3) Interactions are based on springs and classical potentials. 4) Interactions must be preassigned to specific sets of atoms. 5) Interactions determine the spatial distribution of atom-like particles

and their energies.

The objective: to predict the energy associated with a given conformation of a molecule.

A simple molecular mechanics energy equation is given by:Energy = Stretching Energy + Bending Energy

+Torsion Energy + Non-Bonded Interaction Energy

Stretching Energy-

The stretching energy equation is based on Hooke's law. This equation estimates the energy associated with

vibration about the equilibrium bond length

Bending Energy-

The bending energy equation is also based on Hooke's law. This equation estimates the energy associated with

vibration about the equilibrium bond angle The larger the value , the more energy is required to

deform an angle (or bond) from its equilibrium value

Torsion Energy-

The torsional energy represents the amount of energy that must be added to or subtracted from the Stretching Energy + Bending Energy + Non-Bonded Interaction Energy terms to make the total energy agree with experiment

A-controls the amplitude of the curve, n-controls its periodicity,Ф- shifts the entire curve along the rotation angle axis (tau).

Non-Bonded Energy-

The non-bonded energy represents the pair-wise sum of the energies of all possible interacting non-bonded atoms i and j:

Quantum mechanics

Quantum theory uses well known physical constants ,such as velocity of light, values for the masses & charges of nuclear particles to calcaulate molecular properties

The equation from which molecular properties can be derived from schrodinger equation

HΨ=EΨ

Quantum theory is based on Schrodinger's equation:

HΨ=EΨ

Full wave function Electron wave function

• E-energy of the system.• H-is the Hamiltonian operator which includes both

kinetic and potential energy

Quantum mechanics methods are based on the following principles:

Nuclei and electrons are distinguished from each other.

Electron-electron and electron-nuclear interactions are explicit.

Interactions are governed by nuclear and electron charges (i.e. potential energy) and electron motions.

Interactions determine the spatial distribution of nuclei and electrons and their energies.

Softwares : visualization:

Program name Web site

Rasmol www.openrasmol.org

MolVis http://molvis.sdsc.edu/visres

PyMol http://pymol.sourceforge.net

DeepView http://us.expasy.org/spdbv/

JMol http://jmol.sourceforge.net

gOpenMol www.csc.fi/gopenmol/

AstexViewer www.astex-therapeutics.com

Docking:

Program name Web site

ArgusDock www.Arguslab.com

DOCK https://dock.compbio.uscsf.edu

FRED www.eyesopen.com

eHITS www.symbiosys.ca/

Autodock www.scripps.edu

FTDock www.bmm.icnet.uk/docking/ftdock.html

QSAR Descriptor:

Program name Web site

SoMFA http://bellatrix.pcl.ox.ac.uk/

GRID www.moldiscovery.com/

E-Dragon1.0 http://146.107.217.178/lab/edragon

ALOGPS2.1 http://146.107.217.178/lab/alogps/

Marvin beans www.chemaxon.com/

software libraries:

Program name Web site

Chemical development kit http://almost.cubic.uni-koeln.de/cdk/

Molecular modeling toolkit http://starship.python.net/crew/hisen/MMTK/

PerlMol www.perlmol.org

JOELib www.ra.informatik.uni-tuebingen.de/software/joelib/

OpenBabel http://openbabel.sourceforge.net

Advantages of CADD

Time cost Accuracy information about the disease screening is reduced Database screening less manpower is required