drugs : from molecules to man

alpha 2 delta (α2δ) subunit

An accessory subunit of voltage-gated calcium channels that helps modulate their function and trafficking

Accessory subunit

A protein subunit that associates with a primary channel subunit to modulate its properties or localization

Activation gate

The part of an ion channel that opens to allow ion flow in response to a stimulus.

Active (transport)

The movement of ions or molecules across a membrane against their concentration gradient, requiring energy input, often from ATP.

Alpha (α) subunit (voltage gated channel)

The main subunit of a voltage-gated ion channel, forming the pore and responsible for the channel's primary functions

Carrier protein

A membrane protein that facilitates the transport of specific substances across the cell membrane by binding and releasing them.

Ca_V

Short for voltage-gated calcium channel.

Chemical gradient

A difference in the concentration of a specific substance across a membrane

Closed state

A state of an ion channel in which the channel is not conducting ions, even though it may be ready to open

Conductance

A measure of how easily ions flow through an ion channel, influenced by the channel's properties and ion concentration

Cryo-electron microscopy

A technique used to visualize molecular structures at high resolution by freezing samples and imaging them with electrons

Current

The flow of electric charge, in this context, caused by the movement of ions through ion channels.

Dendrogram

A tree-like diagram that shows the relationships between different proteins, often used to compare ion channel families.

Electrical gradient

A difference in electric charge across a membrane, which influences the movement of ions.

Electrochemical gradient

The combined effect of the chemical gradient and electrical gradient that drives the movement of ions.

Electrophysiology

The study of electrical properties of biological cells and tissues, often involving the measurement of ion channel activity.

Gating

The process by which ion channels open or close in response to stimuli such as voltage, ligands, or mechanical forces.

Hydration shell

A layer of water molecules surrounding an ion, affecting its size and interaction with ion channels.

Inactivated state

A state of an ion channel in which it cannot conduct ions, typically occurring after opening.

Inactivation gate

A structure within an ion channel that blocks the pore to stop ion flow during the inactivated state.

Ion channel

A protein that forms a pore in the cell membrane, allowing specific ions to pass through down their electrochemical gradient.

Ion pump

A membrane protein that uses energy to actively transport ions across a membrane against their gradient.

Knock on

A mechanism of ion permeation where an incoming ion displaces another ion already in the channel.

KV

Short for potassium voltage-gated channels.

L type calcium channels

A type of voltage-gated calcium channel involved in long-lasting calcium currents, important in muscle contraction and neurotransmission.

Ligand gated

Refers to ion channels that open or close in response to the binding of a chemical ligand, such as a neurotransmitter.

Membrane dipping domain

A structural domain of an ion channel that enters the membrane on one side but re-emerges on the same side without fully crossing.

Membrane potential

The voltage difference across a cell membrane due to ion distribution.

NaV

Short for sodium voltage-gated channels.

Open state

A state of an ion channel in which the channel is conducting ions.

Passive (transport)

The movement of ions or molecules across a membrane without energy input, driven by the electrochemical gradient.

Pseudo-subunit

A structural domain that mimics a separate subunit but is part of the same polypeptide chain.

Rectification

The property of some ion channels to preferentially allow ion flow in one direction.

Resistance

The opposition to ion flow through a channel, inversely related to conductance.

Resting membrane potential

The electrical potential difference across the cell membrane in a resting, unstimulated state.

Resting stateA state of an ion channel where it is not conducting ions and is ready to be activated. Also known as the closed state

A state of an ion channel where it is not conducting ions and is ready to be activated. Also known as the closed state

Selective permeability

The ability of an ion channel to allow certain ions to pass while excluding others.

Selectivity filter

The part of an ion channel that determines which ions can pass through based on size and charge.

Transmembrane domain

A portion of a protein that spans the cell membrane.

Transporter

A protein that facilitates the movement of ions or molecules across the cell membrane.

Voltage gated (also known as voltage sensitive)

Refers to ion channels that open or close in response to changes in membrane potential.

Voltage sensor

A structural domain of a voltage-gated ion channel that detects changes in membrane potential and triggers channel opening or closing.

Affinity

the tightness of binding of a drug to its target. It is normally measured using KD. As KD goes down, affinity goes up.

Aliquot

A small, measured quantity of a sample. Often used in the context of tissue samples.

B⁠⁠max

the maximum binding of a drug in a sample of tissue. It is a measure the number of binding sites and is usually expressed as an amount e.g. femtomoles, normalized to the total amount of protein in the tissue sample e.g. fmol/mg protein.

Competition binding assay

An experiment where a labelled ligand and an unlabelled competitor ligand compete for binding to a target, used to measure binding affinity and specificity.

Compound library

a large collection of drugs maintained by a pharmaceutical company

Hill-Langmuir Equation

the central equation governing the interaction of a drug with its target

KD

the equilibrium dissociation constant for a drug. It is a measure of affinity and has units of concentration. KD can also be defined as the concentration of drug that produces 50% of maximum binding.

K⁠⁠m

the Michaelis constant. It is one of the parameters in the Michaelis-Menten Equation and is a measure of an enzyme's affinity for its substrate.

Law of Mass Action

A principle stating that the rate of a chemical reaction is proportional to the product of the concentrations of the reactants, applied in drug binding to describe ligand-receptor interactions.

Liquid scintillation counting

A method for measuring radioactivity in a sample by detecting light emitted from a scintillation cocktail when radioactive particles interact with it.

Michaelis-Menten Equation

a version of the Hill-Langmuir Equation that describes how the rate of an enzyme-catalyzed reaction varies with substrate concentration.

Non-specific binding

binding to the non-receptor sites in the assay.

Radioligand

a drug that has had a radioisotope added to it so it can be used as a probe to measure binding at a target protein.

Rectangular hyperbola

A mathematical curve that describes the relationship between ligand concentration and binding in saturation binding assays for a single class of binding sites. It is characterized by a steep rise from the origin after which the curve plateaus.

Saturable

A characteristic of binding where all available binding sites can be occupied at high ligand concentrations, reflecting a finite number of binding sites.

Saturation binding assay

An experiment that measures the binding of increasing concentrations of a labelled ligand to a target, used to determine the total number of binding sites and the affinity of the ligand.

Selectivity

the relative affinity of a drug for one receptor type compared to another. It is usually expressed as the ratio of the two KD values. For example if drug X is 50-fold selective for receptor A vs receptor B, its KD value at receptor B will be 50 times higher than its KD at receptor A.

Specific binding

binding to the receptor sites in the assay

Total binding

the sum of the specific and non-specific binding

V⁠⁠max

the maximal velocity of an enzyme-catalysed reaction. It is the product of the enzyme concentration and the catalytic constant for the enzyme.

Cheng-Prusoff Equation

an equation used to convert IC50 to K⁠⁠i

Competition Binding Equation

an equation used to plot competition binding data

Gaddum Equation

an extension of the Hill-Langmuir Equation that describes competitive binding.

IC50

the concentration of a competing ligand that reduces radioligand binding to 50% of control

K⁠⁠i

the equilibrium dissociation constant for a competing ligand. It is a measure of affinity and is equivalent to KD. The only difference is the method used to determine it.

pK⁠⁠i, pKD

-log K⁠⁠i and -log KD, respectively

Reverse sigmoid curve

a curve shaped like a backwards, spread-out S

Peptide bond

the basic chemical bond that holds amino acids together in a protein

Pharmacophore

the minimum set of chemical features a drug must have in order to bind to its target protein.

Primary structure

the linear amino acid sequence of a protein

Quaternary structure

the assembly of protein monomers to form a functional protein

R group

the side chain of an amino acid that determines its chemical properties

Secondary structure

the folding of sections of the protein into regular patterns like alpha helices

Tertiary structure

the overall folding pattern of a protein monomer

Covalent bond

a strong bond in which atoms share electrons. It is uncommon in drug-target interactions

Dipole

a molecule in which the electrons are unevenly distributed, resulting in one part of the molecule having a slight positive charge and another region having a slight negative charge.

Hydrogen bond

an interaction between a hydrogen covalently bonded to an electronegative atom such as oxygen, and the lone pairs of electrons of another electronegative atom such as nitrogen.

Hydrogen bond acceptor

the electronegative atom that supplies the lone pair in a hydrogen bond

Hydrogen bond donor

the electronegative atom that supplies the hydrogen in a hydrogen bond

Hydrophobic bond

an weak interaction between two hydrophobic molecules. It arises due to a gain in entropy

Ionic bond

an interaction between a cation (an atom that has lost an electron) and an anion (an atom that has gained an electron)

Van der Waals forces

weak interactions between dipoles.

ACE inhibitor (ACEi)

a drug that inhibits angiotensin converting enzyme

ALL-HAT

Antihypertensive and Lipid Lowering treatment to prevent Heart Attack. A clinical trial that heavily influenced US guidelines on how hypertension is treated

Alpha blocker (α-blocker)

an antagonist of alpha adrenoceptors

American Heart Association and the American College of Cardiology (AHA/ACC)

US professional bodies that have collaborated to produce guidelines on treating cardiovascular disorders.

Amlodipine

a dihydropyridine L-type calcium channel blocker used as an antihypertensive

Angina

a heart disorder that occurs when arteries are blocked and heart muscle does not receive enough oxygen. It is a warning sign that the person may have a heart attack.

Angiotensin converting enzyme (ACE)

an enzyme that cleaves angiotensin I (inactive) to yield angiotensin II (active)

Angiotensin II type 1 receptor (AT1R)

the main receptor for angiotensin II

Angiotensin II

a peptide hormone that causes vasodilation and salt and water retention

Angiotensin receptor blocker (ARB)

an antagonist of angiotensin II type 1 receptors

ASCOT trial

the Anglo Scandinavian Cardiac Outcomes Trial. A clinical trial that heavily influenced NICE guidelines on how hypertension is treated

Atenolol

a selective beta adrenoceptor antagonist used as an antihypertensive

Atherosclerosis

clogging of the arteries with cholesterol

Bendroflumethiazide

a thiazide diuretic used as an antihypertensive

Beta blocker (β-blocker)

an antagonist of beta adrenoceptors

Bisoprolol

a selective beta adrenoceptor antagonist used as an antihypertensive