This document discusses computer-aided drug design (CADD) and molecular modeling. It provides a brief history of drug discovery and describes the traditional drug design lifecycle versus the modern CADD approach. The key principles of CADD include molecular mechanics, which uses classical mechanics to model molecule geometry, and quantum mechanics, which is based on solving Schrodinger's equation. The document also lists several common software tools used for tasks like molecular visualization, docking, descriptor calculation, and general molecular modeling libraries. Advantages of CADD are highlighted as reduced time, cost and manpower requirements compared to traditional drug discovery methods.

1. Computer-Aided Drug
Designing $ Molecular
modelling
Presented by
NEHLA YAHCOOB
Dept: pharmaceutical chemistry
Grace college of pharmacy

2. Contents
 History
 Life cycle of drug discovery
› Traditional
› CADD
 Introduction to CADD
 Objectives of CADD
 Priciples involoved in CADD
 Softwares for CADD

3. 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”

4.  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

5. 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.

6. Life Cylce of Drug Design
 Traditional Life Cycle
Synthetic or Natural Compounds
Preclinical Trails
Clinical Trails

7. 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

8. Drug Discovery & Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation &
Scale-up
Human clinical trials
(2-10 years)
FDA approval
(2-3 years)

9. 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 targets
and “personalized” targets
Screening up to 100,000 compounds a
day for activity against a target protein
Using a computer to
predict activity
Rapidly producing vast numbers
of compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing

10. 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

11. 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

12. 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 .
12

13. Principles Governing CADD
 Molecular Mechanics
 Quantum Mechanics

14. 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.

15. 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

16. 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

17. 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

18. 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).

19. 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:

20. 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

21. 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

22. 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.

23. 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

24.  Docking:
Program name Web site
ArgusDock www.Arguslab.com
DOCK https://dock.compbio.uscsf.ed
u
FRED www.eyesopen.com
eHITS www.symbiosys.ca/
Autodock www.scripps.edu
FTDock www.bmm.icnet.uk/docking/ft
dock.html

25.  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/

26.  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/MM
TK/
PerlMol www.perlmol.org
JOELib www.ra.informatik.uni-
tuebingen.de/software/joelib/
OpenBabel http://openbabel.sourceforge.net

27. Advantages of CADD
 Time
 cost
 Accuracy
 information about the disease
 screening is reduced
 Database screening
 less manpower is required