transcription factors (BCl6 in cancer)

signal transduction pathways ( Erk of the mitogen pathway,

and HCK of the SRC family

target based

peptidomimetics

i ) Kidney glycoprotein that stimulates growth of red blood cells in bone marrow
ii) Approximately equal mass of protein (34 kD) and carbohydrate
iii) Used in anemia
iv) Abused by athletes

erythropoeitin

blood factors

growth factors

human growth hormone

cytokines

enzymes (adenosine deaminase

MABS

i) From pituitary gland, used for growth deficiencies in children (nanism, dwarfism)
ii) Hormone originally isolated from human cadaver pituitary (Creutzfeldt-Jakob syndrome)

i) Interleukins (ILs)
    a) Immune system hormones
    b) Interleukin-11 (rhIL-11, oprelvekin, Neumega, Genetics Institue) for treatment of Chemotherapy induced Thrombocytopenia

     ii) Interferons

          a) Generally antiviral, antiproliferative and immunomodulatory effects.
    b) Interferon Beta-1A and 1B: used in treatment of relapsing multiple sclerosis

1) Antigenicity (non self vs self)

2) Stability

3) Drug Delivery

the protein needs to have the appropriate 3D structure

i) chimeric antibodies
    ii) antibodies produced in transgenic mice, rats or yeast

        iii) phage display antibodies

   deamidation: Asn, Gln

   oxidation: Met

   proteolysis: Arg, Lys

   racemization and acid labile: Asp

   disulfide exchange: Cys, disulfide

   aminolysis: Lys

   beta-elimination: Cys, Ser, Thr, Lys

c) Protein often more stable in dry form (lyophilized)

d) Additives to enhance stability

e) Detection of instability

1. SDS page-detecs frafmentation, crosslinking, oligomerization
2. RP-HPLC- deamidation, crosslinking, methionin oxidation, disulfide scrambling
3. IEF- deamidiation
4. potency determination- disulfide scrambline (most important)

hard to give without denaturation (chemical alteration)

rapid liver clearance

E.coli

yeast

mammalian cells

transgenic animal/ plant sources

i) Cheapest
ii) No glycosylation or disulphide formation
iii) Fusion proteins

      iv) Met at N terminus of the
v) Toxins (gram positive bacteria) in E.Coli

i) Relatively inexpensive
ii) Hyper or incorrectly glycosylates

      iii) Correct disulfides 
iv) No toxins
v) Proteins excreted into medium

i) Most expensive of cell-based methods
ii) Produces the most active protein due to proper modifications
iii) Proper post-translational modifications

          glycosylation
    phosphorylation
    disulfides
    propeptide processing

affinity increases (and your able to miss a pair)

you decrease specificity

Target genes at DNA or RNA level that code for

     i) proteins in microorganisms to kill invading organism

     ii) proteins specific to cancer

     iii) any undesired protein

remove the bad bone marrow and replace it with good bone marrow

kill the leukemia cells in the bone marrow

blocks transcription by forming a triplex (three strands)

 works at single strand to form a bubble

during synthesis

at the intron exon junction

inhibits protein initiation factors

at the start codon

and overall interactions

absorption (limited ability to cross membaranes

stability

affinity to binding

co-admin with cationic lipids

encapsulation in carbs

chimeric molecules

alternate backbones (with methylphosphonate)

block 3 prime exonuclease activity

sub the phosphodiesterase bond with a peptide bond

i) Enhance stability and affinity: alpha-anomer at 1' position of 2'deoxyribose

     ii) Resistance to nucleases: 2-OH modifications of ribose including 2'methyl,  2'-allyl, or 2'-fluoro (also enhance affinity)

Hydrophobic modifications of 5' position of pyrimidines that enhance affinity for target RNA or DNA

target HIV

and lower expression  of MDR (transporters that eject drug from cell)

 
2) Identify or create novel molecules to bind to a selected target and elicit a biological response via de novo drug design or database searching techniques

3) Optimize the therapeutic index of an already available drug or lead compound

3D representation of molecules based on graphic or mathematical representations of chemical structures

treat electrons explicitly

limited to 100 atoms

deals with atom as smallest particle

every atom interacts with ever other atom

allos you to study a system with millions of atoms

V total=Vinternal+Vexternal

where Vinternal=Vbonds+Vangles+Vdihedrals

Vexternal=Vvanderwaals+Velectrostatic

double bond has 2 peaks (a peakseperated by 180 degrees)

in a single bond you have 4 peaks (each peak seperated by 60 degrees)

the closer you get the less your attractive forces are

the closer you are the greater your repulsive forces

energy (atom positions)

energy minimizations (atoms positions, forces)

molecular dynamic simulation (atom simulation, forces, atomic velocities)

geometric arrangment of functional groups

can be determined by 3d structure, knowledge of ligand

this is a way to develop a pharmacophore by

a) Prepare a 3D lattice of grid points encompassing the binding site

b) Determine interaction energy of different types of functional groups with binding site at each grid point.

c) Select favorable interaction sites

1. determine solvent accessible surface of binding pocket (spheres)
2. generate a negative image of receptor based on spheres
3. determin sphere distances of the negative image
4. convert sphere distances to atom distances
5. compare atom distances with actual atom distances
6. select ligands with greatest overlap
7. calculate ligand receptor interaction energies

1. develop a grid for binding site (include electrostatic, VDW)
2. generate a structures (first is the core, then you build up on it then randomly select one of the top 25%
3. synethesise compounds

B) Identify specific positions of certain functional groups etc. that my be related to a known pharmacophore

C) Database screening for similar compounds in chemical databases (avoid synthesis!).

Rigid geometry of receptor and ligand

  Ligands often treated as flexible

  Multiple conformations of receptor can partially overcome rigid representation

Inherent assumptions and simplifications in molecular mechanics

1) diffusion controlled encounter

2) initial Michaelis complex

3) desolvation of both inhibitor and binding site

4) conformational changes of both inhibitor and binding site upon binding

5) correct orientation between drug and receptor binding site

a method to compare 1 drug receptor complex to another

K_eq2/K_eq1=K_receptor/K_solution

1. in a computer you change molcule 1 that is bound to the receptor to molecule 2 in the receptor
2. this is done by change the equilibrium and force constants in small steps

1) Anticancer agents

2) Antibacterials

3) Non-surgical abortions

glutamic acid

benzoic acid

bridge

pteridyl

the drug target is the pteridyl

1. amino pteridine (competative inhibitor)
2. methotrexate (just adds a cabonyl to the amino group of the pteridyl )
3. trimethoprim

• we evolved with them
• chemistry is similiar
• diverse plants and diverse chmistry as a result
• tend to be nourshing and supportive

using a plant that mimics human anatomy or disease

ex 

Walnut for brain health •

Red juice of bloodwort for blood disorders •

Kidney-shape leaves of Hepatica to treat  •

kidney disease

1. arrow poison
2. religous rituals (phyostigma
3. belladonna oracle of apollo, and cosmetics
4. as corecers drug

wormwood against malaria, fever

toad skin for heart conditions (digitalis glycosides)

used ephedra sinica as stimulant

16th century book on its meds

regarded as the greatest form of healing med in islam

now it is none to have many of the nutrients reccomended by the FDA

40% of american population

73% of cancer patients

herbal medicine

ingested

aroma

ointments

labeling issues

no quality control

misinformation in literature

supply issue

quality issue

safety issue (herbal drug food interactions)

caffeine

followed by ephedra

long life elixer

reverses gray hair, ED, vaginal discharge

it may lower cholesterol

mild laxative

weight loss

lower blood pressure

reduce cholesterol

fight arthritis pain

relief sore throat

Ginko

echinacea

garlic

ginseng

soy bean

saw palmetto

st john's wort

valerian

bilberry

black cohosh

increase blood flow

possibly effective in dementias

only safe for a year use

produces nonspecefic immune activation

use with flu

12 weeks

8 weeks in autoimmune disease

active ingredient allicin will lower lipids and cholesterol

interacts with lasix, inhibit barbitutes

may increase BP and overuse can give insomnia headaches etc..

sever depression, suicidal tendencies, sever agitation, prego, may induce seratonin syndrome with triptans, mat interfere with cyclosporin, inhibits CYP450

may cause photosensitvity

about 25%

74% of anticancers

78% of anti-bacterial

natural products produced in cells

primary metabolites

secondary metoblites

1. Not more than  ƒ5 H bond doners (OH and NH groups) 
2. hydrogen bond acceptors  10 (5X2) Not more than (notably N and O) 
3. A molecular weight under 500 (5x100)  ƒ
4.   A partition coefficient logP 5 under
5. < then 10 rotatable bonds

pyrrolizidine alkaloids

phorbal esters

aristolochic acids

it can be teratogenic, carcinogenic, hepatoxic

contains pyrrolizodine alkaloids

is nephrotoxic and hepatotoxic

contains NDGA

it is a pseudoaldosteronism (retains Na, water and depletes K)

this is dose dependent

 Avoid using herbs in 

infants, children, pregnant women, 

nursing mothers, patients w/ daisy 

allergies, patients on multiple 

medications

they can alter transporters

they can alter CYPS

alter absorption

compete with drug targets

classification

diagnosis of mechanisms of drug action

prediction of activity (in congeneric series)

lead compound optimization

1. the ortho position will have minimal transferability
2. the meta position will have an inductive effect (may favor unionized thus smaller Ka) a -σ
3. if you have a para substituant then you will have resonance effects(increasing Ka) a +σ

the posative slope is an electron withdrawing group

the negative group is electron donating

E_s

this says that the impact of the substiuant is dependent on size( the term is always negative and the more so it is the more steric hinderance)

Consideration of need to cross membranes

Blood brain barrier

Lipophilicity (hydrophobicity)-this will dictate how fast it can cross the barrier

∏

if it is + then it will be more hydrophobic

if it is- it will be more hydrophillic

1. ∏ you will want this to be negative, but not so much to where it wont go into the lipid bilayer (more hydrophillic)
2. σ you will want this to be posative (electron withdrawing)

hard to extrapolate byond your list

predictions are limited to rings

you will need 5 compounds for every term you use

it's like an on off switch

I is substituant and J is location

• basically trying to find your drug without using a training set
• measure then add what you think is needed measure then keep doing this till you are close to what you want