PHC5005 Chap.6 Drug Targets, Receptors and Selectivity
Drug Targets, Receptors and Selectivity
The drug's side of the exchange
Pharmacodynamics studies how drugs act at molecular, cellular and whole-body level, and the mechanisms that produce those actions. The course's starting principle is modest and important: drugs do not create new biological processes, they modulate existing ones by amplifying, fine-tuning or blocking them.
To do that a drug must bind a target, and the character of that target, where it sits, and how tightly and selectively the drug holds it explain most of what the drug does, including its adverse effects.
The kinds of target
Drug targets are macromolecules, overwhelmingly proteins and less commonly nucleic acids, found in the cell membrane, cytosol, nucleus or extracellular space.
The lecture's examples span cell-surface receptors (propranolol at beta-adrenoceptors), intracellular receptors (dexamethasone at the glucocorticoid receptor), transporters (fluoxetine at the serotonin reuptake site), pumps (omeprazole at the proton pump), structural proteins (paclitaxel at tubulin), enzymes (lovastatin at HMG-CoA reductase), membrane lipids (polymyxins) and DNA (cisplatin).
Receptors themselves fall into four families linked to their effectors in different ways: ligand-gated ion channels, G protein-coupled receptors, kinase-linked receptors and nuclear receptors.
Newer modalities, antibodies, gene therapy, CAR T cells, siRNA and antisense drugs, extend the idea of a target into immunology and genetics.
How binding happens
Most drug-receptor binding uses weak, reversible, non-covalent forces, ionic and dipole interactions, hydrogen bonds, van der Waals forces and hydrophobic interactions, which demand a close structural fit.
Covalent binding is stronger and often irreversible. Structure-activity relationships identify the pharmacophore, the arrangement of groups needed for activity, which is why ACE inhibitors, beta-blockers and calcium channel blockers each share a recognisable core.
Binding obeys the law of mass action, and the equilibrium dissociation constant, the concentration that occupies half the receptors, measures affinity: the smaller the constant, the greater the affinity.
Selectivity and specificity
Specificity is a chemical idea, a ligand binding only one receptor type.
Selectivity is a pharmacological one, a preference for the intended target that holds at low concentrations and weakens as the concentration rises.
Many side effects are selectivity failures: a non-selective beta-blocker risks bronchospasm in asthma, diphenhydramine dries the mouth through cholinergic blockade, and terfenadine's affinity for the cardiac hERG channel caused dangerous QT prolongation that its successor fexofenadine avoids.
Receptors in disease and treatment
Receptor autoantibodies and receptor gene mutations cause disease, and receptor testing guides therapy.
The lecture's breast cancer case moves from biopsy to hormone receptor staining and HER2 testing and ends with endocrine therapy plus an anti-HER2 antibody, a treatment choice made by reading receptors.
What this chapter covers
- 01
Drugs as modulators of existing biological processes
- 02
Classes of drug target and where they are located
- 03
The four receptor families and new therapeutic modalities
- 04
Non-covalent and covalent drug-receptor forces
- 05
Structure-activity relationships and the pharmacophore
- 06
Affinity and the equilibrium dissociation constant
- 07
Selectivity, specificity and off-target adverse effects
- 08
Receptor testing in the treatment of breast cancer
Worked example · free
Explaining the difference between two antihistamines
- 1Compare the two drugs' affinity for the intended target.
- 2Compare their affinity for the cardiac potassium channel.
- 2State the clinical consequence and the general principle.
Key terms
- Receptor
- A protein that detects one of the body's own signalling molecules and converts that detection into a change in cell behaviour.
- Ligand
- Any molecule, endogenous or not, that binds to a receptor.
- Pharmacophore
- The active chemical moiety of a drug, a set of groups at defined distances that binds the receptor.
- Affinity
- The ability of a drug to bind its target, quantified by the equilibrium dissociation constant.
- Dissociation Constant
- The drug concentration that occupies half of the target at equilibrium; a smaller value means higher affinity.
- Selectivity
- A drug's relative preference for its intended target, strongest at low concentration and eroded as concentration climbs.
- Specificity
- The chemical property of a ligand that binds only one type of receptor.
- Allosteric Site
- A binding site on a receptor different from the site used by the endogenous ligand.
- hERG Channel
- The cardiac KV11.1 potassium channel whose blockade by some drugs prolongs the QT interval.
Drug Targets, Receptors and Selectivity FAQ
Are all drug targets receptors?
No. Receptors are one class. Drugs also act on enzymes, transporters, pumps, structural proteins, membrane lipids and nucleic acids. The course's examples include lovastatin inhibiting HMG-CoA reductase, fluoxetine blocking serotonin reuptake and cisplatin interfering with DNA replication.
What makes a covalent drug different?
Covalent bonds carry much higher energy than the ionic, dipole, hydrogen-bond, van der Waals and hydrophobic forces behind most binding. A covalently bound drug often produces irreversible inhibition, as afatinib does at the EGFR receptor,.
How can a drug be selective yet still cause side effects?
Selectivity is relative and depends on concentration. At therapeutic levels a drug may prefer its intended target, but as concentration rises it occupies other targets too. The course states directly that selectivity decreases with increasing drug concentration.
Why does a smaller dissociation constant mean stronger binding?
The dissociation constant is the concentration needed to occupy half the receptors at equilibrium. A drug that achieves half occupancy at a lower concentration holds its receptor more tightly, so affinity is proportional to the reciprocal of the constant.
How do receptors guide cancer treatment?
Testing the tumour for hormone receptors and HER2 amplification identifies which drugs have a target. In the course's case, a hormone receptor-positive, HER2-amplified breast cancer is treated with tamoxifen or an aromatase inhibitor and with the anti-HER2 antibody Herceptin, with chemotherapy.
What is the difference between the lock-and-key and induced-fit models?
The lock-and-key model, from 1894, pictures a rigid binding site into which only a matching molecule fits. The induced-fit model, from 1958, lets the site change shape as the ligand binds. The course uses both to explain why drug-receptor binding can be selective.
Exam move
Make a two-column card for every drug named in this lecture: its target class on one side and one clinical consequence of hitting that target on the other. Then add a third column for any second target it also hits. That third column is where most adverse-effect questions come from.
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