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Drugs: From Molecules to Man - Lecture 4 (09/02/2018)
Drugs target a variety of cellular components. Some bind to lips, some to DNA. Some act only via physicochemical properties such as osmosis.
However, most of the drugs we will meet in this unit act on protein targets. For this reason, after briefly touching on non-protein targets, we will spend most of this lecture looking at the chemical nature of proteins and how bonds form between proteins and small drug molecules.
We will also consider the importance of drug shape, with a focus on the phenomenon of stereoisomerism.
Lipids as drug targets
The drug disrupts the lipid structure and have indirect action on proteins.
Lipids form conducting pathways across the membrane and alter the electrochemistry of the cell.
Drug interactions with lipids are relatively rare. They can occur through two potential mechanisms.
Firstly, drugs might dissolve in the lipid bilayer and alter its structure. Because proteins are also dissolved in the bilayer, the change of structure of the bilayer can alter the structure of the protein. This was originally thought to be how general anaesthetics worked, but increasingly it is being recognised that these drugs work by acting directly on proteins.
Another way that effects on membranes can occur is if the drugs form conducting pathways across the membrane and so disrupt the electrochemistry of the cell. Some antibiotics work this way.
DNA as drug targets
The drugs covalently modify DNA bases and intercalate between the bases to disrupt reproduction of the cell.
There is little specificity in this as they act on binding sites not receptors.
Drugs can act on DNA directly (as distinct from actions mediated by nuclear hormone receptors that we met in previous lectures). They can do this either by wedging themselves between DNA bases (intercalation) or modifying DNA bases covalently. This causes mutations in the DNA when the cell reproduces and kills it. Such drugs are used as cytotoxic anti-cancer drugs as they primarily affect dividing cells. Some toxins/mutagens also work this way e.g. the dye ethidium bromide that was used to stain nucleic acids in electrophoresis gels.
Both lipids and DNA binding sites show little specificity. They are not receptors. Receptor Proteins
Receptor proteins form specific interactions with drugs at a limited number of binding sites.
Receptor proteins (and other protein-based targets) normally form very specific interactions with drugs. Further, the fact that there is a finite number of each type of protein in a cell means that there is a limited number of binding sites. Binding will therefore be saturable.
The Relative Sze of the Drug vs the Receptor
Text books often show cartoons of drugs binding to receptors that look like the one on the left.
However, the true picture is rather different. Receptors are large complexes with RMMs in the range of 100s of kDa. Drugs are normally much much smaller - typically 100s of Da.
Drug binding Domains
The drug interacts with a small part of the receptor.
This difference in size means that a drug will only interact with a small part of the receptor complex. We term this part the binding site or binding domain.
The drugs make specific bonds with the binding domains.
The binding energy of the drug produces a conformational effect.
When a drug binds to a receptor, it has to form chemical bonds with the protein.
There is binding energy associated with this interaction and this energy is turned into a conformational effect on the receptor complex.
Either the receptor will be stabilized in a particular conformation or it might induce the receptor to change conformation. It is this conformational effect that defines the drugs mechanism.
Examples of conformational changes include: Channel opening/closing, Receptor activating and G-protein dissociation.
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