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BIOC 3600Antiviral Drug Design

Dr. J. Jaegerjj@bmb.leeds.ac.uk

33031

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Aims and Objectives1. To gain an understanding of the processes involved in drugdiscovery and drug design.2. To understand the differences between potential inhibitors,

drugable lead compounds and marketed drugs Whatmakes a blockbuster drug??

3. To learn about different drug design strategies exemplifiedby viral proteases and polymerases.4. The concept of drug resistance and drug cocktails.

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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 anddesign 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.

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Rationales for Drug DesignHBV HCV HIV

Prevalence350 M chronic

(2000 M total)220 M 36 M

UK carriers1 in 1000-3000

(no screening)

60000040370

(1999)

Treatment some No sufficient

Vaccine Vaccine No No

Transmission Bodily fluids Bodily fluids Blood

Viability outside

host7 days hours 30+ days

Risks33%

(shared needles)

3.5%

(shared needles)

0.3%

(shared needles)

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Rationales for Drug Design Tuberculosis is a global threat affecting 1/3of worldpopulation with latent infections. 50% of HIV patients developTB. TB cases are on the rise and approximately 2 million peopleeach year die from the infection. The spread of HIV/AIDS and the emergence of multidrug-resistant TB are contributing to the worsening impact of thisdisease. It is estimated that between now and 2020, approximately1000 million people will be newly infected, over 150 million

people will get sick, and 36 million will die of TB- if control isnot further strengthened.2002

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Drug Design CycleTarget

structure

Proposedligands

Compound

libraries

Lead

compounds

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Realistic Design Cycle

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The Good, the Bad & the UglyThere are important differences between a given compoundfrom 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

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The Good, the Bad & the Ugly IIIndustry 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?)

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Blockbuster DrugsClaritinan anti-allergy drugwith sales reaching$3 billion in 2000(nearly 1/3 ofSchering Ploughsrevenues .

Prilosecan ulcer drugproduced by AstraZeneca, sold over$6.2 billion worthglobally in 2000alone.

Zantacalso an ulcer drug.Glaxo sold $9 billionworth of globally, butlost patentprotection in 1997.Drug sales in the USin 1997 totaledmore than $69.4billion.

HIV drugsIn 1998 in the US,NRTIs accounted for$885 million insales, PIs $865million and NNRTIsfor $100 million.The market in therest of the world isabout $2 billion(1998).

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Molecular WeightSize 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

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Molecular weight

0 100 200 300 400 500 600 700 800

Leads (W.Sneader)

Drugs (W.Sneader)

World Drug IndexWDI: 3800 - 4100 drugs

with calculable properties

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Number of heavy atoms

0 10 20 30 40 50 60 70

Leads (W.Sneader)

Drugs (W.Sneader)

World Drug Index

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Number of aromatic rings

0 1 2 3 4 5 6 7 8

Leads (W.Sneader)

Drugs (W.Sneader)

World Drug Index

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Trends

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Trends

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

NOTELog P = 1 means 10:1 Organic:Aqueous

Lipophilicity andpartition coefficients

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Log D, Distribution CoefficientsLog 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 ofthe lipophilicity of a drug at the pH of blood plasma.

Distribution CoefficientD = [Unionised]

(org)

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

Log D = log10 (Distribution Coefficient)

logP and logD

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Lipophilicity andpartitioning coefficient (logP & logD)

-20 -15 -10 -5 0 5 10 15 20 25

Leads (W.Sneader)

Drugs (W.Sneader)

World Drug Index

By definition log refers to the neutral form of the compound.

logP

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Trends

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The rule of fivePoor 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 10Substrates for transporters and natural products are exceptions.

Zantac

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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. toleratedno-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

Bound/Fr

ee

high

affinity

low

affinity

1/Kd

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Aims and Objectives1. To gain an understanding of the processes involved in drugdiscovery and drug design.2. To understand the differences between potential inhibitors,

drugable lead compounds and marketed drugs Whatmakes a blockbuster drug??3. To learn about different drug design strategies exemplifiedby viral proteases and polymerases.4. The concept of drug resistance and drug cocktails.

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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 anddesign 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.