Dr. J.

Jaeger
jj@bmb.leeds.ac.uk
33031

Aims and Objectives
1. To gain an understanding of the processes involved in drug
discovery and drug design.
2. To understand the differences between potential inhibitors,
drugable lead compounds and marketed drugs. What
makes a blockbuster drug??
3. To learn about different drug design strategies exemplified
by viral proteases and polymerases.
4. The concept of drug resistance and drug cocktails.
1. Blockbuster drugs, some general rules for drugs, lead compounds
and drugability, Mw, solubility, lipophilicity, logP, rule of five, bio-
availability, efficacy, specificity, toxicity, biologics
Synopsis: Lectures 1 - 6
2. High-throughput screening methods, formats, robotics, virtual
screening, QSAR, DOCK, SPROUT, Combichem.
3. HIV/AIDS: protein structures and drug targets, screening and
design approaches for HIV-1 protease (Pr) drug classification, drug
resistance and prospects.
4. HIV/AIDS: reverse transcriptase (RT), screening and design
approaches for RT drugs, HIV RT drug classes. Next generation
drugs, future prospects.
5. Hepatitis B and Hepatitis C virus, HBV transcriptase
drugs and resistance. HCV Pr drug development.
6. Herpes virus polymerase, antiviral drugs and specificities,
development and improvements, HSV drug resistance.
Rationales for Drug Design
HBV HCV HIV
Prevalence
350 M chronic
(2000 M total)
220 M 36 M
UK carriers
1 in 1000-3000
(no screening)
600000
40370
(1999)
Treatment some No sufficient
Vaccine Vaccine No No
Transmission Bodily fluids Bodily fluids Blood
Viability outside
host
7 days hours 30+ days
Risks
33%
(shared needles)
3.5%
(shared needles)
0.3%
(shared needles)
Rationales for Drug Design
Tuberculosis is a global threat affecting 1/3 of world
population with latent infections. 50% of HIV patients develop
TB.
TB cases are on the rise and approximately 2 million people
each year die from the infection.
The spread of HIV/AIDS and the emergence of multidrug-
resistant TB are contributing to the worsening impact of this
disease.
It is estimated that between now and 2020, approximately
1000 million people will be newly infected, over 150 million
people will get sick, and 36 million will die of TB - if control is
not further strengthened.
2002
Drug Design Cycle
Target
structure
Proposed
ligands
Compound
libraries
Lead
compounds
Realistic Design Cycle
The Good, the Bad & the Ugly
There are important differences between a given compound
from a library, selected lead compound and a marketed drug.

The drugability depends on a number of criteria such as:

specificity, solubility, liphophilicity, bioavailability
molecular weight, flexibility, synthetic route,
drug target and tissue specificity, blood brain barrier
The Good, the Bad & the Ugly II
Industry has additional requirements:

Inexpensive to synthesize and manufacture
Distinct clinical endpoints
Reimbursable
No global regulatory or patent issues
To market 3 - 5 years from discovery
(more like 7 - 10?)
Blockbuster Drugs
Claritin

an anti-allergy drug
with sales reaching
$3 billion in 2000
(nearly 1/3 of
Schering Ploughs
revenues .






Prilosec

an ulcer drug
produced by Astra
Zeneca, sold over
$6.2 billion worth
globally in 2000
alone.




Zantac

also an ulcer drug.
Glaxo sold $9 billion
worth of globally, but
lost patent
protection in 1997.

Drug sales in the US
in 1997 totaled
more than $69.4
billion.




HIV drugs

In 1998 in the US,
NRTIs accounted for
$885 million in
sales, PIs $865
million and NNRTIs
for $100 million.

The market in the
rest of the world is
about $2 billion
(1998).
Molecular Weight
Size or molecular weight of a potential drug affects

stability, ease of synthesis?
bioavailability, dosage, antigenicity
solubility, transport across membranes?
success in clinical trials
and FDA approval!
Mw: 650 D
Mw: 170 D
Molecular weight
0 100 200 300 400 500 600 700 800
Leads (W.Sneader)
Drugs (W.Sneader)
World Drug Index
WDI: 3800 - 4100 drugs
with calculable properties
Number of heavy atoms
0 10 20 30 40 50 60 70
Leads (W.Sneader)
Drugs (W.Sneader)
World Drug Index
Number of aromatic rings
0 1 2 3 4 5 6 7 8
Leads (W.Sneader)
Drugs (W.Sneader)
World Drug Index
Trends
Trends
Log P and Partition Coefficients

The partition coefficient is defined as the ratio of concentration of a
given neutral molecule in the aqueous phase to the concentration in an
immiscible organic solvent.

The Log P will vary according to the conditions under which it is
measured and the choice of partitioning solvent.

Partition Coefficient
Partition Coefficient, P = [Organic] / [Aqueous]
Log P= log10 (Partition Coefficient)

NOTE
Log P = 1 means 10:1 Organic:Aqueous

Lipophilicity and
partition coefficients
Log D, Distribution Coefficients

Log D is the log distribution coefficient at a particular pH. This is not
constant and will vary according to the protogenic nature of the
molecule. Log D at pH 7.4 is often quoted to give an indication of
the lipophilicity of a drug at the pH of blood plasma.

Distribution Coefficient

D = [Unionised]
(org)

[Unionised]
(aq)
+ [Ionised]
(aq)

Log D = log10 (Distribution Coefficient)
logP and logD
Lipophilicity and
partitioning coefficient (logP & logD)
-20 -15 -10 -5 0 5 10 15 20 25
Leads (W.Sneader)
Drugs (W.Sneader)
World Drug Index
By definition logP refers to the neutral form of the compound.
logP
Trends
The rule of five
Poor absorption or poor permeation often occur when there are:

More than 5 H-bond donors.
Mw is over 500 D.
The CLog P is over 5 (or MLOGP is over 4.15).
The sum of Ns and Os is over 10.

Substrates for transporters and natural products are exceptions.
Zantac
Measures of Drug Efficacy
Affinity, specificity and selectivity
- hitting the right target?
- multiple sites?
- Scatchard plots
Safety, toxicity (cell based)
- other targets?
- side effects?
Dose, delivery, formulation
max. tolerated no-effect tox.
oral, IV
Pharmacokinetic profile
Drug metabolism
determines distribution, disposition,
breakdown/elimination, ADME

0
10
20
30
40
50
60
70
0 50 100 150 200
Bound
B
o
u
n
d
/
F
r
e
e
high
affinity
low
affinity
1/Kd
Aims and Objectives
1. To gain an understanding of the processes involved in drug
discovery and drug design.
2. To understand the differences between potential inhibitors,
drugable lead compounds and marketed drugs. What
makes a blockbuster drug??
3. To learn about different drug design strategies exemplified
by viral proteases and polymerases.
4. The concept of drug resistance and drug cocktails.
1. Blockbuster drugs, some general rules for drugs, lead compounds
and drugability, Mw, solubility, lipophilicity, logP, rule of five, bio-
availability, efficacy, specificity, toxicity, biologics
Synopsis: Lectures 1 - 6
2. High-throughput screening methods, formats, robotics, virtual
screening, QSAR, DOCK, SPROUT, Combichem.
3. HIV/AIDS: protein structures and drug targets, screening and
design approaches for HIV-1 protease (Pr) drug classification, drug
resistance and prospects.
4. HIV/AIDS: reverse transcriptase (RT), screening and design
approaches for RT drugs, HIV RT drug classes. Next generation
drugs, future prospects.
5. Hepatitis B and Hepatitis C virus, HBV transcriptase
drugs and resistance. HCV Pr drug development.
6. Herpes virus polymerase, antiviral drugs and specificities,
development and improvements, HSV drug resistance.