Pharmaceutical

Chemistry
Department

Drug Design
)412/6(

Section (1)

Introduction
Introduction to the Art of Drug
Design
The Drug Discovery and Development Process

Molecular Modeling and Computer-aided Drug Design (CADD)

Energy Calculation

Energy Minimization

Bioactive Conformation & Conformation Generation

The Drug Discovery
Process

Laboratory session 1
Let’s recall

Laboratory session 1
 1. Target Identification
The major drug targets:
1. Proteins Remember:
which was the
2. Nucleic acids
?major target
3. Carbohydrates
4. Lipids

Laboratory session 1
2. Lead Identification
Where do Leads come from?
isolation of serendipity
natural products

computer aided
Existing drugs Screening approach
drug design

The most fruitful

pathway
 Isolation of
Serendipity The Screening natural Rational Drug Existing Drugs
Approach products Design

High-throughput Virtual Screening (VS),

Screening, HTS In Silico Screening

• Physical • Molecular modeling +

• large compound virtual chemical libraries +
libraries structural data of biological
• sophisticated, fully target  assess affinity of
automated systems compounds to the target.
• “hits”, validated by • model not actual data 
repeated testing quality of results depends
• Time consuming on quality of the model.
• virtual “hits”  physically
validated in biological
Laboratory session 1 screening
 3. Lead Optimization

Using molecular modeling, one can know the structure of the binding site &/or
determine the essential features for binding to the site, design the new analogues
according to these features, and predict the possible interactions of the designed
compounds with the targets prior to synthesis.

Laboratory session 1
CADD: Computer Aided
Drug Design

Laboratory session 1
What is computer-aided
?drug design (CADD)
• It is science that employs several
advanced techniques and
computational tools to simulate the
behavior of biological systems and their
interactions with (drugs- ligands), for
the design of new drugs.
• CADD is the use of molecular modeling
in drug design.

Laboratory session 1
What is Molecular
Modeling?
• Molecular modeling encompasses all
theoretical methods and computational
techniques used to model or mimic the
behavior of molecules (small & large)

Laboratory session 1
What is Molecular
Modeling?
• The accuracy and quality of CADD techniques
depends on the extent of their ability to
simulate the real behavior of the molecular
system.
• This ability is based upon:
1- the complexity of the techniques used (the
parameters and equations used to construct
the model)
2- the computational power of the device
used.
Laboratory session 1
What is Molecular
Modeling?
Just like what ???

Laboratory session 1
 Why CADD?
• Drug design goal: to predict whether a molecule will
bind to a target, and if so how strongly.
• In the field of drug design, molecular modeling can
help in:
1. Predicting the 3D structure of the small molecule
ligands,
2. And 3D model of the target (biological
macromolecules )
3. Predicting the possible interaction between the
ligand and the target and numerically express the
strength of binding.
Laboratory session 1
 The main aim of CADD is Simulating
The interaction between the drug and biological target

17
 Why CADD?
• In the field of drug design, molecular modeling can help in:
4. Calculating the energy of molecules and their
representative conformers.
5. Predicting the different states of biological
macromolecules, for example: the active and inactive
states of receptors.

Laboratory session 1
 Why CADD? (Cont’d)
CADD may be used at any of the following
stages of drug discovery:
1. Hit identification using virtual screening
2. Hit-to-lead optimization of affinity and
selectivity
3. Lead optimization: optimization of other
pharmaceutical properties while
maintaining affinity.

Laboratory session 1
Energy Calculation &
Energy Minimization

Laboratory session 1
?How Can Molecular Energy Be Calculated

Molecular Quantum
Mechanics Mechanics

Laboratory session 1
 Molecular Mechanics -1

A mechanical model of the molecule is made, in which:

- Atoms are represented by balls, whose mass is
proportional to their relative atomic masses (mass of
electrons is neglected relative to the nuclear mass)
- Bonds are represented by mechanical springs, their
stiffness corresponds to the nature of the bond.

Laboratory session 1
 Cont. Molecular Mechanics

• Each bond has an optimum (standard) bond length

and bond angle, above or below which the energy
of the molecule increases.
• For example: E = Σ K (L-L0)2

But how can the standard bond length, angle

electrostatic forces…etc be determined??
How is the energy calculated??
By Forcefield
Laboratory session 1
 Forcefield

• Force field is a set of equations and parameters

that allow simulation of the action of forces affecting
the structure.
• Parameters: as atom type (C, N, O, sp3 C, sp2 C ,sp
C,..), the optimum bond length between each pair of
atoms, optimum bond angles of different bonds,
atomic radii,….etc.
• In order to calculate energy of a molecule, the
molecule is typed with a force field. Then, it is
perceived as a system of balls and spring and its
energy can be calculated.
Laboratory session 1
 Cont. Molecular Mechanics

There are several types of force fields as MM2, MM3 and MM4
that are used for small organic molecules, and AMBER and
CHARMm designed for large macromolecules

Advantages Limitation
• Simple, economic, and • MM reveal nothing
rapid. about electron
• Can be performed on distribution in
molecule with several molecules. Therefore,
thousands of atoms they can‘t be used in
(large molecules/ chemical reactivity or
proteins). selectivity.
Laboratory session 1
 Quantum Mechanics -2

• In quantum mechanics, the energy of a given

system (a molecule or sets of molecules) is
obtained by solving the Schrödinger equation that
defines the wave function of the molecular system.

• It considers the dual nature of electrons (wave and

particle ).

Laboratory session 1
 Quantum Mechanics -2

• Advantages of quantum mechanics calculation:

- Very advanced and accurate method.

• Limitation of quantum mechanics calculation:

- Requires very advanced hardware and very long
computation time.
But how much time???
• Hybrid QM/MM techniques are also employed
for protein calculation and are now widely used
for analysis of enzymatic reactions.
Laboratory session 1
Bioactive Conformation &
Conformation Generation

Laboratory session 1
 Conformation Definition
• Conformation/ Conformer is the 3D geometry of a
molecule due to rotation around its single bonds.
• A molecule has of a set of conformers in 3D that
differ in their energies.

Laboratory session 1
 Bioactive Conformer
The target has 3D geometry
So a certain 3D geometry of the drug can bind to the target

Bioactive conformer
3D arrangement of the drug that binds to the biological target due to
.complementarity in shape and features

Laboratory session 1
 Energy Diagram
.The Bioactive conformer of one of the low energy conformers

Energy diagram: A relation between the possible conformers

and their corresponding energies to get the bioactive conformer

Laboratory session 1
 Energy Minimization

• E minimization aims for making the 3D structure (of

the ligand or the target) -that you deal with- a more
realistic one.
• Minimization treatment consists of successive
alterations of the geometry of the molecule until a
minimum is found.
• The minimization is terminated when it is not
possible to find a conformer of lower energy than
the current well considered.
• ‘Local minimum trap‘, where the molecule is
trapped in local minimum conformation and no
extra minimization technique can retrieve he global
minimum conformer.Laboratory session 1
 AX
A BZ
A xxx Z
X xxx Z
B

Any change in conformer X will

lead to energy elevation
Laboratory session 1
 Conformation Generation

• Conformation generation of a certain molecule aims

for defining the global minimum and other
representative low energy conformers, thus
increasing the probability of getting the (expected)
bioactive conformer among them.

• These set of conformers are then subjected to other

molecular modeling techniques that can predict
their biological action.

Laboratory session 1
 Conformation Generation

1-Systematic:
• Systematic exploration of all possible conformations,
by systematic variation in each single/ rotatable bond
in the structure.
• There are an infinite number (not 360) of possible
conformations for any given rotatable bond,
conformational explosion in compounds with several
rotatable bonds.
• For a compound with 2 rotatable bonds:
There are 129600 conformers !!!!
Laboratory session 1
 Conformation Generation

2-Random search:
• These methods start with several initial conformers
that undergo minimization procedures, till they reach
a minimum, maximizing the opportunity to achieve
the global minimum
3-Simulation:
• Simulating the molecule at different temperatures
allow the molecule to cross the energy barriers. Thus,
subsequent cooling may achieve the global minimum
conformer.

Laboratory session 1
Post Protocol questions (1)
– Page 24
1. What is meant by ‘molecular modeling’?

2. Describe the role of CADD in the discovery

of new active agents.

3. What are the limitations of virtual

screening?
Laboratory session 1