Pharmaceutical DrugsPharmaceutical Drugs

Chemistry 199LPharmaceutical Drugs

(Chapter 19)

Pain relievers and fever reducer: aspirin

(S bl k) (Aspirin)1893Few

(Sunblock)1827

Stomach distress& bleeding

• Analgesic (pain reliever)Antipyritic (fever reducer)

side-effect& bleeding

• Antipyritic (fever reducer)• Anti-inflammatory• Anticoagulent: heart attack and stroke preventionAnticoagulent: heart attack and stroke prevention

Inhibits production of prostaglandins (pain messengers)

Limitation of Aspirin

(A i i )

• Still causes some intestinal bleeding

(Aspirin)

(not recommended by people facing surgery, child birth, etc.)

• not effective for severe pain, e.g., migraine headachel d l d i i l di d• prolonged use can lead gastrointestinal disorders

• overdose• allergic reactions• allergic reactions• Reye’s syndrome for children with flu or chickenpox

Aspirin substitutes(Overuse can lead to

Now banned Tylenol

(Overuse can lead to liver/kidney damage)

Advil Aleve Orudis KT

Cold remedies: Antihistamines

When allergens bind to surface of certain cells, they trigger release of histamine,y ggwhich causes redness, swelling and itching

Antihitamine blocks releases of histaminebut some also enter the brains and act on cellsbut some also enter the brains and act on cells controlling sleep, causing drowsiness.

Other cold remedies: Cough suppressants and decongestantsAll treat only symptoms, not the causeEffect of vitamin C has been observed; reason still unknown

Infectious diseases

19001995

Antibacterial drugs: sulfa drugsAntibacterial drugs: sulfa drugs

(Mimic PABA)

(PABA)

Discovered in 1935 by Gerhard Domagk (German chemist)

Needed by bacteria to make folic acid(PABA)

Chemical mimic-type poison for bacteriay g ( )

An antibiotic: penicillin

A colony of Penicillium notatum, the mold from which penicillin ismold from which penicillin is derived:

1928: first discovered by Alexander Fleming

1941: first tried on human

Antibiotics: soluble substancesAntibiotics: soluble substances (often derived from molds or bacteria) that inhibit the growth of other microorganism

https://www countway harvard edu/chm/rarebooks/exhibits/stones/scans/mold jpg

Some bacteria cell walls are made of mucoprotein polymersPenicillin prevents crosslinking between protein monomers and therefore

https://www.countway.harvard.edu/chm/rarebooks/exhibits/stones/scans/mold.jpg

p g pcell wall synthesis.

Cells of higher animals (including human) do not have mucoprotein cell walls

Antibiotics: penicillins

There are many penicillins

Other antibacterial drugs

Fluoroquinoloneuo oqu o o e

bind to bacterial

inhibitsribosomes inhibitsbacterial DNAreplication

Viruses

VirusesDNA viruses (DNA/proteins)

enter host cell direct it to make viral proteinse te ost ce d ect t to a e a p ote s

RNA viruses (RNA/proteins)RNA viruses (RNA/proteins)

enter host cell replicate viral RNA induce synthesis of viral proteinssynthesis of viral proteins

R t i (RNA/ t i )Retroviruses (RNA/proteins)

enter host cell synthesize DNA from the RNA (reverse transcriptase) synthesis of viral(reverse transcriptase) synthesis of viral proteins

Anti-Viral Drugs

HIV drugs:•Nucleoside analogs (AZT)Nucleoside analogs (AZT)•Reverse transcriptase

inhibitors•Protease inhibitors•Protease inhibitors

Anti-cancer drug:f CDiscovery of Cisplatin

1845 i di i di hl l ti (II) ( i l ti ) fi t th i d• 1845: cis-diaminedichloroplatinum(II) (cisplatin) first synthesized• 1965: Barnett Rosenberg, inhibition of cell growth by cisplatin• 1970: Cisplatin prevents DNA transcription.

1972 Cli i l t i l f i l ti• 1972: Clinical trials of cisplatin.

Anti-Cancer drugsgProblem: How to selectively kill cells

One solution: target rapidly dividing cells (antimetabolites)

Drug DesignDrug Design

• What is a drug? How do they work?What is a drug? How do they work?• What features does a drug need to have?

For efficacy?• For efficacy?• For safety?• For cost-effectiveness?For cost effectiveness?

• How do we find/invent/improve drugs?

TerminologyTerminology• Target: the biomolecule, g

complex, cell, etc. that the drug is meant to impact

• Library: a large collection of substances that may be useable as drugs

• Hit: a substance that gives the desired result during screening; a potential drug

Drug discovery/development

E l 1980’Rational drug design

Early 1980’sg g

or Computer aided design (CAD)

Specificity• How do we achieve specificity?

H d h ifi it ?• How do we enhance specificity?

• What targets are we good at?

Structure-based CAD

Structure ofStructure of working drugs

Chemistry

Modeling

Enhancing specificityg p y• use proteins as drugs

• antisense (nucleic acids)

• structure-based drug design

• SCREENING

Ad ances in speed q alit and di ersitAdvances in speed, quality, and diversity

• High-throughput techniques

• Combinatorial libraries

Targetsg

• enzymes• enzymes

• dimeric/domain recognitionWhat we’re • antibodies

• nucleic acids

What we regood at

• multimeric complexes

High throughput screeningHigh-throughput screeningRational design requires lots of supporting data…

Instead, screen EVERYTHING.

Modern advances:• robotics• library developmenty p• information systems• microvolume chemistry• combinatorial library development• combinatorial library development

1990: 100 compounds/week2003: 100,000 compounds/DAY

Modern drug discoveryg y

Target ID Hit Target HitTarget ID generation validation development

Choice VerificationChoiceof

library

VerificationBioinformatics Bioassay

Bioassay Choicef

yof

libraryProteomics

High-throughput screeningHigh throughput screening (HTS)

• Discovery• Hit developmentApplications• Preliminary assessment of

metabolism & toxicity

pp

• Test substance supplyComponents • Bioassay development & implementation

• Informatics

Components

• Informatics

Test substance supplyTest substance supply• Library development• Combinatorial chemistry• Natural products

St t b d d i• Structure-based design

Define targetdimensions

Computationalanal sis

Use relevantlibraries

Optimizedimensions analysis libraries

Bioassay developmentBioassay development• Whole animals• Tissue Th h tTissue• Cellular function• Protein function

Cost

Relevance

Throughput

Specificity• Gene expression• Genome sequence

Relevance Specificity

Define targetdimensions

Computationalanalysis

Use relevantlibraries

Optimize

InformaticsInformatics

• StorageStorage

• Retrieval

• Cross-referencingCross referencing

D fiDefine targetdimensions

Computationalanalysis

Use relevantlibraries

Optimize

Another big challenge: d d lidrug delivery

http://www.pharmj.com/editorial/19990828/pictures/parenteralFig5.gif