BMS 123 · Common Core (Tronc commun)Section 5.4 · Pharmacodynamics: mechanisms and receptors

Section 21 of 27

Drug–receptor binding

Describe the lock-and-key model and the binding equilibrium, name the seven binding forces and their reversibility, and separate affinity from intrinsic activity.

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Why this matters

Binding is the moment a drug becomes active. Everything that follows — how strong the effect is, how long it lasts, why one drug can be displaced and another cannot, why toxicity appears when a drug stays too long — is decided by how the drug sits on its receptor. Affinity and intrinsic activity then tell you two different things about that drug, and confusing them is one of the commonest mistakes in pharmacology.

What you need to know first

You need the idea from 5.3 that a receptor is a protein with a small binding site, and the everyday notion of a chemical bond. The seven binding forces are described here one by one, so no chemistry beyond that is assumed.

Words to know (6)

Affinity: The ability of a drug to combine with its receptor, that is, how readily it binds and how long it stays bound. A high-affinity drug binds receptors at low concentration.
Intrinsic activity: The capability of a drug to evoke a pharmacological response once it has combined with the receptor. An antagonist has affinity but zero intrinsic activity.
Binding site: The small portion of the receptor that interacts with the drug; also called the recognition site. Only the binding site touches the drug, not the whole receptor.
Residence time: The duration for which the drug–receptor complex persists, which decides how long the effect continues. A long residence time explains an effect that outlasts the plasma level.
Agonist: A drug that possesses both receptor affinity and intrinsic activity, so it switches the receptor on. Morphine is an agonist at opioid receptors.
Antagonist: A drug that possesses receptor affinity but no intrinsic activity, so it occupies the receptor without activating it. An antagonist blocks the effects of the endogenous ligand.

One idea at a timeIdea 1 / 6

In one sentence The receptor is a lock and the drug is a key: only a small part of each actually touches, forming a drug–receptor complex.

The lock-and-key model

The basic concept of the drug–receptor interaction can be described as a lock-and-key model. The receptor is the lock and has a particular portion, the binding site or recognition site, into which the drug — the key — can fit, forming a complex. The drug is attracted to the receptor and the two are held together by reversible forces. Only a small portion of the receptor and a small portion of the ligand are involved: the rest of the receptor holds its shape, and the rest of the drug molecule may serve mainly to carry the pharmacophore to the right place. A perfect key opens the lock; an imperfect key fits but does not turn it.

For example

Salbutamol is shaped so that it fits the β₂ receptor and switches it on. A β-blocker such as propranolol fits the same family of receptors but does not switch them on, so it blocks what would otherwise happen.

Think of it like

The key and the lock is the standard comparison because it captures shape and fit. Its limit is important: a real receptor is flexible, it changes shape when the drug binds, and the complex forms and breaks many times a second rather than clicking once into place.

Pause and check yourself

In the lock-and-key model, which parts actually touch?

Show the answer

The binding site or recognition site of the receptor and the pharmacophore of the drug. The rest of each molecule is not directly involved in the contact.

Read detailed explanations

Occupancy, Kd and why affinity is not potency: The reversible equilibrium can be read quantitatively. At equilibrium the ratio of the dissociation and association rates gives a constant, the dissociation constant Kd, which has units of concentration. Its practical meaning is simple: when the free drug concentration equals Kd, half of the receptors are occupied. A small Kd therefore means high affinity, because very little drug is needed to occupy half the receptors. From this, occupancy at any concentration can be written as [D] divided by (Kd + [D]). Two lessons follow. First, occupancy always approaches one as the concentration rises, however low the affinity, which is why a weak drug can still produce a maximal effect if enough of it is given. Second, and more important, occupancy is not the same as effect. A tissue may need to occupy only a small fraction of its receptors to produce a half-maximal response, because it holds receptors in reserve; and a partial agonist may occupy every receptor and still produce only a sub-maximal response. Affinity therefore sets the concentration needed for binding, while intrinsic activity and the tissue’s receptor reserve decide what that binding achieves. That distinction is the bridge to the dose–response curves of Unit 6.
Covalent drugs in practice: Covalent bonding is rare in drug–receptor interactions because it removes the clinician’s ability to stop an effect by stopping the drug. When it is used, it is used deliberately. Aspirin acetylates cyclo-oxygenase and so blocks the production of prostaglandins and thromboxane for the whole life of the platelet that carries the enzyme, which is why a single small dose affects clotting for several days. Omeprazole is transformed in the acidic environment of the parietal cell into a reactive species that binds the proton pump covalently, which is why acid suppression outlasts the drug’s presence in the blood. In both cases the long effect is the therapeutic point. The cost is also visible: a covalent drug cannot be competitively displaced, so an overdose cannot be reversed by giving more of the natural agonist, and recovery depends on the body making new protein. This is the same behaviour that will reappear in section 5.5 as non-competitive antagonism. When you see a drug whose effect clearly outlasts its measured half-life, the first hypothesis to test is that it binds covalently or has an exceptionally long residence time.

Explore the diagram

Look at the whole drawing first. Then select one numbered part and connect it to the idea you just read.

The lock-and-key model of binding

The receptor is the lock, the drug is the key, and only a small part of each actually touches: the binding site of the receptor and the pharmacophore of the drug. The equilibrium below shows how the complex forms and breaks.

New to diagrams? Read this first

Look at the whole drawing once without clicking anything. Ask yourself only: what kind of picture is this (a comparison, a route, a sequence, a table)?
Press Play, or use the arrows, to move through the numbered parts in order. The drawing stays still; only the highlight moves.
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01 / 6Receptor (the lock)

If the drawing is wider than this panel, scroll it sideways. Labels stay readable; the numbered explanations below show the same ideas.

Receptor (the lock)

A protein or glycoprotein that receives chemical signals. Its shape is fixed for a given receptor, and only molecules that fit the recognition site can occupy it. The analogy stops here: a receptor is flexible and can change shape when a ligand binds.

Schematic, not to scale. The lock-and-key image is a teaching analogy, not a physical description: real receptors flex, and real binding is a constant exchange described by association and dissociation rates rather than a single click.

Key points to remember

The lock-and-key model describes how a drug fits the binding site of its receptor to form a complex.
Binding is reversible and can be written [D] + [R] ⇌ [D–R], with association and dissociation rates.
Hydrogen, hydrophobic, van der Waals, ion–dipole and dipole–dipole forces are weak and easily reversible.
Ionic bonds are strong but reversible; covalent bonds are “irreversible”, delay elimination and prolong the effect.
Affinity is the ability to bind; intrinsic activity is the ability to evoke a response.
Agonists have affinity plus intrinsic activity; antagonists have affinity only.

Go deeper

Worked example

Explaining why one effect outlasts the other. Two patients receive different drugs that act on the same receptor. In the first patient, the effect fades smoothly a few hours after the plasma level falls. In the second, the effect continues for days after the drug can no longer be detected in the blood. You must explain the difference using binding, residence time and the nature of the bond.

Write the equilibrium for each drug: [D] + [R] ⇌ [D–R]. In both patients the forward reaction stops when the drug concentration falls, so the difference cannot come from the forward step alone.
Look at the backward reaction. In the first patient the complex splits readily, because the drug is held by hydrogen bonds, hydrophobic contacts and van der Waals forces — all weak and reversible.
In the second patient the drug has formed a covalent bond. Under biological conditions that bond is not broken, so the complex cannot split when the plasma level falls.
Translate that into residence time: the first drug has a short residence time and its effect tracks the concentration; the second has an effectively infinite residence time and its effect tracks the lifetime of the protein, not of the drug.
Draw the clinical conclusion. The second drug will keep acting — and keep producing toxicity — long after the prescriber has stopped giving it, so its dose and its indication must be chosen with that in mind.

The plasma concentration tells you how much drug is present, not how long the receptor stays occupied. Affinity and the strength of the bond together decide that, which is why two drugs with identical blood levels can have completely different durations of action.

Common misconception

A frequent and costly beginner error is to assume that a drug with high affinity must be a powerful drug. Affinity only describes binding. A molecule can bind its receptor extremely tightly and produce no response whatever, because it has no intrinsic activity — that is exactly what an antagonist is. Potency and efficacy are separate questions, dealt with in Unit 6.

Check your reasoning

Two drugs bind the same receptor with the same affinity, but drug X produces a large effect and drug Y produces none. What must be different between them, and what would you measure to prove it?

Reveal an answer

Their intrinsic activities differ: X is an agonist and Y is an antagonist. Equal affinity means equal occupancy at a given concentration, so the difference cannot come from binding. To prove it you would measure occupancy — for example by displacement of a labelled ligand — alongside the response, and show that equal occupancy gives unequal effect.

Where this comes from

BMS 123 General Pharmacology II lecture notes · Part Two, §3.1 The “Lock-and-key” analogy; §3.2 Binding forces; §3.3 Affinity and intrinsic activity

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About this course and its sources

Bilingual lessons organised from the supplied BMS 123 General Pharmacology II lecture notes (Principles of Pharmacokinetics and Principles of Pharmacodynamics). Diagrams are original educational schematics; pharmacology, nursing and French-language review are pending.