Drug discovery ch. 7 - Drug resistance and drug synergism

Drug resistance

When a formerly effective drug dose is no longer effective

What is drug resistance from?

Natural selection

Exogenous resistance

New proteins developed to protect organism from drugs

Endogenous resistance

Occurs by mutation

Altered target enzyme/receptor

Mutation of an amino acid residue; drug binds poorly, but substrate binding unchanged

Overproduction of the target enzyme/receptor

Induction of extra copies of the gene encoding the target protein is another mechanism for drug resistance

Proteasome

Complex of proteases that degrade proteins that are tagged for degradation

Inhibition causes ___ of ___ ___, leading apoptosis

Accumulation of waste proteins

Apoptosis

Cell stress and death

Overproduction of the substrate/ligand for the target protein

Competitively blocks the ability of the drug to bind at the active site

Increased drug-destroying mechanisms

Produce new enzymes, increase quantities of existing enzymes, or produce other substances to degrade or isolate the drug

What are the approaches when making a drug-destroying enzyme?

Make an analog that binds poorly to the new enzyme, alter structure of drug so it is not modified by the new enzyme, and inhibit the new enzyme with a second compounds

Decreased drug (prodrug)-activating mechanism

A compound that is enzymatically converted to the active substance after its administration

Activation of new pathways circumventing the drug effect

If the drug inhibits an enzyme that block production of a metabolite, the organism could induce a new metabolic pathway that produces the same metabolite

Reversal of drug action

Can repair damaged cells

Altered drug distribution ot the site of action - Modified cell membrane

A cellular organism excludes the drug from the site of action by preventing cellular uptake of the drug

What is modified cell membrane effect with?

Charged and polar drugs

Altered drug distribution to the site of action - Efflux pumps

Transmembrane proteins that act as transporters to carry drugs out the cell before they elicit their therapeutic effect

Multidrug resistance pumps

Broad specificity transporters that efflux a wide range of drugs against microorganisms and tumor cells

Drug synergism

When the therapeutic effect of two or more drugs used in combination is greater than the sum of the effect of the drugs individually

Inhibition of a drug-destroying enzyme

A drug-resistant enzyme can be inhibited by a second drug that is co-adminstered

Sequential blocking

Inhibition of two or more consecutive enzymes in a metabolic pathway

Inhibition of targets in different pathways

A combination of drugs that blocks both pathways that creates the metabolite that causes resistance

Efflux pump inhibitors

Used when a drug is being effluxed a transporter protein

Use of multiple drugs for the same target

The chance of an organism being resistant to multiple drugs exponentially increases