Post on 13-Apr-2017
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