Molecules & Medicine Exam 3

pharmacophore

molecular framework that carries the essential features responsible for a drug’s biological activity

structural (2D) pharmacophore

defines minimum skeleton connecting important binding groups

para-amino-benzoic acid PABA

intermediate in the bacterial synthesis of folate (vitamin Bx)

most bacteria require it

prontosil

red dye/prodrug

antibacterial

ACE inhibitors

2D pharmacophore example - captopril (anti-hypertensive)

3D pharmacophore

defines relative positions in space of important binding groups

morphine

3D pharmacophore example

generalized bonding type pharmacophore

defines relative positions in space of the important binding interactions which are required for activity

• HBA/HBD

• Van der Waals interactions

• ionic interactions

active conformation

conformation adopted by a drug when it binds to its target and produces the desired effect

• identification of this is required to identify 3D pharmacophore

classical isosterism

response to the observation that different atoms with the same valence electron structure had similar biological effects

isosteres

• replace a functional group with a group of the same valency (OH replaced by SH, NH2, CH3)

• leads to more controlled changes in steric/electronic properties

• may affect binding and/or stability

isosterism example

NH2 to OH

classic isosteres examples

biosteres

• replace a functional group with another group which reatains the same biological activity

• not necessarily the same valency

biosteres example

antipsychotics

• improved selectivity for D3 receptor over D2

• pyrrole ring substituted for amid group

biostere purpose

• drug design

  • exchanging one for the other may enhance the desired biological or physical properties of a compound without making significant changes in chemical structure

  • reduces toxicity, change bioavailability, or modify the lead compound

carbonyl

carboxylic acid

amide

ester

hydroxyl

catechol

pyridine

benzene

optimizing binding interactions

aims:

• to increase activity and reduce dose levels

• increase selectivity and reduce side effects

varyl alkyl substituents

the alkyl group in a lead compound may interact with hydrophobic region in the binding site

• vary in length and bulk of group to optimize interaction

varyl alkyl substituent examples

selectivity of adrenergic agents for beta-adrenoceptors over alpha-adrenoceptors

extension - extra functional groups

aim:

• to explore target binding sites for further binding regions to achieve additional binding interactions

• ACE inhibitors

Enalapril

ACE converts peptide hormone angiotensin I → angiotensin II which vasoconstricts blood vessels

on the World Health Organization’s list of essential medicines

extra functional groups examples

nerve agents and medicines

• addition of quaternary nitrogen

• extra ionic bonding interaction capacity

• increased selectivity for cholinergic receptor

• mimics quaternary nitrogen of acetylcholine

chain extension/contraction

rationale:

• useful if a chain is present connecting two binding groups

• vary length of chain to optimize interactions

Chain extension/contraction example

N-Phenethylmorphine: optimum chain length = 2

the compound is ~ 8-14x more potent than morphine as a result of modification

ring expansion/contraction

rationale: to improve overlap of binding groups with their binding regions

ring expansion/contraction example

ring variations

rationale:

• replace aromatic/heterocyclic rings with other ring systems

• often done because of patent reasons

• sometimes result in improved properties

ring variations example

nevirapine (antiviral)

simplification

rationale:

• lead compounds from natural sources are often complex and difficult to synthesize

• may help structure to fit in binding site easier and increase activity

• may be more selective and less toxic if things are removed

simplications

• things are removed

• functional groups that may be unnecessary but help to retain the pharmacophore

simplifcation disadvantages

• too much may result in decreased activity

• may have more conformations

• more likely to interact with more than one target binding site

• may result in increased side effects

rigidification

• endogenous lead compounds are often simple and flexible

• fit several targets due to different active conformations

• results in side effects

rigidification strategy

• limits conformations (restraint)

• increases activity (more chance of desired active conformation being present)

• increases selectivity (less chance of undesired active conformation

atropisomerism

stereoisomers that arise because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to roation that is high enough to allow isolation of individual conformers

prodrugs

inactive compounds which are converted to active compounds in the body

prodrug uses

• improves membrane permeability

• prolongs activity

• masks toxicity and side effects

• varying water solubility

• drug targeting

• improves chemical stability

prodrugs for membrane permeability

esters: used to mask polar and ionisable carboxylic acids, used when a carboxylic acid is required for target binding

trojan horse strategy

prodrug designed to mimic biosynthetic building block, transported across cell membranes by carrier proteins

ex: levodopa for dopamine

masking polar groups to prolong activity

reduces rate of excretion

ex: azathioprine for 6-mercaptopurine

adding hydrophobic groups to prolong activity

drug concentrated in fat tissue

slow removal of hydrophobic group

slow release into blood

to mask toxicity and side effects

the groups responsible are covered

used when those groups are important for drug activity

ex: salicylic acid for aspirin

to lower water solubility

used for foul tasting orally active drugs

they don’t break down as fast on the tongue

ex: palmitate ester of chloramphenicol (antibiotic)

to increase water solubility

prevents dissolvation in fat globules in gut (better interaction with gut wall overall)

ex: lysine ester of estrone (better absorbed orally than estrone)

for drug targeting

used to deliver/activate the therapeutic agent at a specific disease site (like a tumor)

can use the distinct acidic microenvironment created by tumors/sites of infection to activate

ex: hexamine to treat urinary infections

to increase chemical stability

protects the active pharaceutical agents from premature degradation, hydrolysis, oxidation, etc.

ex: hetacillin for ampicillin (alpha-NH2 group attacks beta-lactam ring on ampicillin where the nitrogen in heteracillin is locked)

synergism

drugs which have a beneficial effect on the activity or pharmacokinetic properties of another drug

sentry drug

a drug that is added to ‘protect’ another drug

ex: carbidopa which inhibits the decarboxylase enzyme in the peripheral blood supply, protecting L-Dopa

peptides as drugs

act as neurotransmitters, hormones, and enzyme substrates

imporant lead compounds

disadvantages: susceptible to digestive/metabolic enzymes, pharmacokinetic properties often unsatisfactory, difficulty crossing cell membranes

peptidomimetics

• modify peptide-like drugs to make them less peptide-like

• increase resistance to digestive and metabolic enzymes

• increase water solubilty

• increase oral absorption/bioavailability

replacing a susceptible peptide bond

replace with stable functional group (should mimic important features of the target bond)

• planar

• H-bonding with target binding site

disguising a peptide bond

N-methylation

planar peptide bond retained

• beneficial if forms important interaction to digestive/metabolic enzymes

• detrimental if forms important interaction to target binding site

altering stereochemistry

inverting an asymmetric center

• replace L-amino acid with D-amino acid