Drug Design

Lecture I
Mahmoud Salama , PhD
Faculty of Pharmacy
Department of Pharmaceutical Chemistry
Email: Mahmoud.salama@bue.edu.eg

20th Century: Antibiotic Era

20th Century: NSAIDS

Research and Development Phases

The whole process takes 10 -1 5 years

Cost = $ 1.3 billion
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Research and Development Phases

The ideal drug candidates should be:

1- Potent
2- Selective
3- Physical and Metabolic stable
4- Non-mutagenic
5- Non- teratogenic
6- Non- Toxic
7- Patentable
8- Manufacturable

Two Billion Dollar Lesson

Two Billion Dollar Lesson

Two Billion Dollar Lesson

Important Definitions
Drug: A chemical compound with specific pharmacological activity
and minimal toxicity.
Effective
Less toxic
Highly selective
Molecular Target: A target responsible for executing the biological
functions and in case of dysfunction, this will lead to evolution of
clinical problems.

Important Definitions

Receptor: A protein molecule embedded within the surface of the

cellular plasma membrane receiving signals from outside the cell.
Hit: A selected series of active compounds either synthesized or
naturally occurred.
Hit To Lead: Development / Optimization of the hit compounds
towards generation of the most active prominent candidate.
Lead: An active prominent compound to enroll clinical trials.
All New Chemical Entities 1981-2010

S*
4%

NM
20%

S
29%

V
6%

B
15%

ND
22%

N
4%

Biological

Natural Product

Semi-synthetic modification to
Natural Product

ND

Totally Synthetic
Totally Synthetic but with
natural product
pharmacophore

S*

Natural Mimic

NM

Vaccines

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Drug - Receptor Interaction

Molecular Recognition:
Recognition of the biological molecular target and
interacting with ligands (potential drug candidates),
then visualization in three dimensional model.

KEY LOCK MODEL

INDUCED FIT MODEL

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1- Finding Lead Compounds

Natural Products Screening

High Through output Screening

Side Effects Screening (Pharmacovigilance)
Serendipity
Natural Neurotransmitters
Computer Aided Drug Design

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Finding
Lead
Compounds
Natural Materials Screening
Plant Origin

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Finding
Lead
Compounds
Natural Materials Screening
Plant Origin

Microbiological Origin

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Finding Lead Compounds

High Through Output Screening (HTS)

Side Effects Screening (Pharmacovigilance)

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Finding Lead Compounds

Serendipity
Clonidine
Sildenafil
Minoxidil
Natural Neurotransmitter

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Finding Lead Compounds

Computer Aided Drug Design
Rational Drug Design via identifying molecular target
Design of active hits based on pharmacophore
Pharmacophore: Chemical segment of the molecule which is
essential for binding with the receptor to produce Pharmacological
activity
Optimization of Hit to lead compound
Prediction of binding affinity of ligands to the molecular target prior
synthesis
Advantages??

Disadvantages??

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2- Pharmacophore Identification
Pharmacophore: Chemical segment of the molecule which is essential for
binding with the receptor to produce Pharmacological activity

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3- Hit Design
The design is followed by biological and pharmacological evaluation.
High Through Output Screening: An automated method for screening a
library of compounds (10,000 up to 2 million compounds) biologically for
generation of Hit compounds.

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4- Hit to Lead Generation

Not all Hit compounds are eligible to be drug candidates.

Hit to Lead generation elucidates the structural activity relationship (SAR)

for further optimization.

Tyrosine Kinase Inhibitor

Used for treatment of Leukemia
SAR elucidates the importance of
substituents in the meta position for activity
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4- Hit to Lead Generation

The biological data derived for the synthesized hits will help to elucidate
mathematical model correlating between the activity and chemical
properties (descriptors)
Based on this mathematical model, the activity for virtual library can be
predicted prior to its synthesis, this approach is called Quantitative
Structural Activity Relationship (QSAR)

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4- Lead Optimization
A library of lead compounds is generated synthetically to be biologically
evaluated for optimization and generation the most active drug candidate
prior to the clinical trials.

Newly approved FDA Tyrosine Kinase Inhibitor

Used for treatment of Chronic Mylogenious Leukemia
Newly available in the market
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Challenges related to drug discovery

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