Medicinal Chemistry

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Test 1: Drugs,Targets, Pharmcodynamics, and Pharmcokinetics
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1

Irreversible Inhibition

- Blocks enzyme activity permanently

-reacts w/ and makes covalent bonds w/ enzyme

2

suicide inhibitors

- bind to enzyme; the enzyme catalyzes change in the inhibitor

- the changed inhibitor covalently binds to enzyme

3

Isozymes

- have similar (homologous) sequences

- same overall structure

- may be found in different tissues and/or respond to different stimuli

4

IC50

Inhibitor concentration at which you have 50% enzyme activity

-usually looking for low-mid nanometer range

5

What Happens When Cell Signaling Goes Wrong?

-Diabetes -allergies/asthma

-chronic stress -cancer

-autoimmue -neurological

-heart disease

6

agonists

-mimics natural signal molecule

- activates receptor

7

antagonist

-binds to receptor, but does not activate it

- typically blocks binding and/or activation of receptor to natural signal

8

Designing agonist (and antagonist)

-Must consider induced fit

-correct size

-correct binding groups

-correct orientation of binding groups

9

Competitive antagonists

-binds to an alternate site ( "allosteric site")

-causes receptors to change shape

-prevents signal binding

-takes advantage of natural allosteric (regulatory)

10

Umbrella Effect Antagonists

-Binds near normal pocket

-part of molecule blocks binding pocket

11

inverse agonists

- the receptor must have some amount of basal activity on its own (no signal)

-Inverse agonists prevent signal;activated activity, as well as basal activity

12

Desensitization

-cause by prolong exposure to agonists

-deactivate receptor through phosphorylation

-endocytosis to get receptor away from surface

-decrease synthesis of receptor

13

sensitization

-caused by prolonged exposure to antagonists

-increased synthesis of receptor

14

Intercalating Agent

-Contain planar aromatic/heteroaromatic ring systems

-fit between layers of base pairs and disrupt shape of helix

-VOW interactions w/base pairs, possible ionic/dipole interactions with backbone

-preference is shown between minor and major grooves

-prevents replication and transcription

15

Non-Intercalating Topoisomerase Poisons

-Stabilize normally transient cleavable complex formed between DNA and topoisomerase

-may prevent cleaved DNA from repair

16

Alkalating Agents

-Highly electrophilic compounds that react with nucleophilic groups on DNA, making covalent bonds

-Alkylation changes hydrogen bonding groups on base

-poor selectivity can also alkylate proteins

17

Metallating Agents

-central platinum atom covalently bound to 2 chlorine and 2 NH3

-stable outside of body

-inside body chlorine displaces water

-Positively charged complex binds strongly to DNA

18

Chain Cutters

-acts as false substances

-incorporated into growing DNA chain,but does not allow extension

19

3 Necessary Characteristics of Chain Cutters

-must be recognized by DNA template

-must have triphosphate groups

-structure must make it impossible to add another nucleotide

20

Regulators of Transcription

-hairpin polyamide structure w/heterocyclic ringd

-interacts w/DNA (regulator elements) base pairs blocking transcription

21

Drugs acting on rRNA

-prevents translation of mRNA into protein

22

Agents Blocking Transport Proteins

-Agents binding to transporter proteins prevent re-uptake of neurotransmitters

-results in increased levels of affected neurotransmitters

-results in similar effects as using an agonist for neurotransmitter

23

Agents Acting on Biosynthetic Building Blocks

-caps building block used in synthesis of bacterial cell wall

-contains peptide chain which forms H-bonds with target

-Vancomycin acts as a binding site for the building blocks

-makes the target transpeptidase produce weaker peptidoglycan making bacteria more vulnerable and less stable

24

Chain terminators

-inhibits translation

-puromycin is an antibiotic which stops protein synthesis

-mimics aminoacyl-tRNA molecules used during translation

-binds to ribosomes and prevents aminoacyl-tRNA from binding

25

Protein Binding Inhibitors: Triofibin

Thought to mimic tri-peptide sequence in fibrinogen

-binds to integrin that normally binds fibrinogen

-blocks interaction between integrin and fibrinogen

used as anticoagulant

26

Agents Interacting with cell membrane lipids

-Drugs acting on cell membrane lipids (anesthetics& some antibiotics)

-Action of amophotericin B (antifungal agent)

  • Builds tunnel through cell and drain membrane
27

Agents Interacting with cell membrane lipids

-peptide antibiotics thought to form a helix in the cell membrane

-two helices aligned end to end form an "escape tunnel"

-hydrophobic exterior interacts w/cell membrane lipids

-hydrophilic interior allows uncontrolled passage of ions

28

Agents Interacting with cell membrane lipids

-cyclic structure w/alternating ester and amide links

-hydrophobic residues on exterior

-polar carbonyl groups in interior

-valinomycin has to stack to form a pore

29

Agents Interacting with cell membrane lipids

-acts as an ion carrier

-hydrophobic groups on exterior interacts with membrane lipids

-carbonyl groups interact w/ K+ ions from cell

30

Agents Acting on Carbohydrates

-Carbohydrates play important role in cell recognition, regulation, and growth

-potential targets for the treatment of bacterial and viral infection, caner and autoimmune disease

-carbohydrates act as antigens

31

3 Phases of drug action

Pharmaceutical phase - dissolution

Phamacokinetics phase - absorption & transport

Pharmacodynamics phase - interaction w/ targets

32

Factors that Affect Ability of drug to reach target

ADME

-Absorption

-Distribution

-Metabolism

-Excretion

33

Absorption

Orally administrated drugs

- have to withstand low pH in stomach

-have to pass through 2 cell membranes to get to small intestine

-to get to blood stream - pass between cells of capillary wall

-must have balance of hydrophobic/hydrophilic character

34

Lipinski's Rule of 5

MW< 500 Da

greater than 5 HBD groups

greater then 10 HBA groups

logP< +5

35

Exceptions to Lipinski's Rules

-small polar molecules may fit btwn intestinal wall cells

- molecules that 'hijack" transporter proteins (that aid in absorption of nutrients from diet)

36

Polar drugs may be given by injection

  • or ones that are sensitive to digestion

drugs that are polar can be used to get target intestinal disease

37

Average Human Being

10 billion capillaries

200m2 of surface are

no cell is more than 25 micrometers away from a capillary

takes 1 min for a drug to be distributed around the body

38

Factors affecting distribution

extremely hydrophobic molecules get absorption into adipose tissue

ionized drugs may bind to other macromolecules

drugs that bind plasma porteins

39

Blood Brain Barrier (BBB)

-capillary walls are less "leaky"

-capillaries are coated in fatty layer

-polar molecules have a hard time passing

40

Placental Barrier

-separates mother/fetus blood

-has to allow movement of nutrients and wastes

-most drugs can pass through

41

metabolism

-body tries to get rid of foreign molecules by enzyme rxn

-mostly in liver

-some in blood, intestinal wall, other organs

-most drugs metabolites are less active than the original drug

42

Excretion

Major routes:

Kidneys (urine) Skin(sweat)

bile (intestines) Breast milk

Lungs (breath)

43

Administration of drugs

Oral Inhalation

sublingual Injection

recal implants

epitheial ( topical, patch, eye drops)

44

Drug Metabolism

-make molecules more polar to facilitates/promotes excretion

-orally-dosed drugs pass through the liver ("first pass")

45

Phase I

-adds a polar functional group("handle") to molecule

-may remove a nonpolar group to reveal a more polar one

-cytochrome P450 enzyme

46

Phase II

Addition of a polar molecule to an existing polar group

47

Cytochrome P450 protein

-hemoproteins= contain heme ring (w/ iron)

- split oxygens = monooxygenases

-33 knwon CYP proteins

-every individual has different population of CYP protiens

48

Drugs that affect CYP activity

Phenobarbitone = activates/enhances

cinmetidine = inhibits

St. john's wort = enhances

-can cause problems w/under or over dosing

49

Drug food interaction

Enhances activity of CYP proteins

Cigarette smoke

brussel sprouts

inhibits activity of CYP proteins

grape fruit juice

50

Competitive Inhibition

-binds to active site

-Km goes up

51

Uncompetitive Inhibition

- Km and Vmax values go down

-substrate must bind first

52

mixed inhibition

-Km value goes up and Vmax goes down

-can bind to just an enzyme and can bind to an ES complex

53

Noncompetitive inhibition

-Vmax value goes down and Km value stays the same