Foundations: The Language of Drugs and Targets

Comprehensive practice flashcards covering drug-target interactions, binding kinetics, selectivity, target classes, and drug-likeness based on the Foundation lecture notes.

How is a drug (specifically for IVL) and its target defined?

A drug is a chemical compound (small molecule) that binds to a specific protein, while a target is the specific protein (receptor, enzyme, or ion channel) the drug is designed to bind to correct a disease's behaviour.

What is the difference between the 'lock-and-key' and 'induced fit' models of drug binding?

Lock-and-key refers to a molecule's shape being complementary to a target's pocket, while induced fit means the pocket flexes and both partners adjust to accept the molecule.

What is a 'cryptic pocket' in the context of the ATX3 program?

A pocket invisible in the static structure of a protein that only opens transiently as the protein moves.

Define Agonist, Antagonist, and Modulator modes of action.

An Agonist activates the target (turns it ON); an Antagonist blocks the target (keeps it OFF); a Modulator binds to a secondary site to tune the target's activity up or down (allosteric).

What is an aggregation modulator and how does it differ from traditional modes?

It is a molecule that binds a misfolding protein to change its tendency to clump. Unlike agonists or antagonists, there is no signal to switch on or off; it targets the process of protein clumping.

How is binding affinity measured and what do the values indicate?

Affinity is measured by the dissociation constant ($K_d$) or inhibition constant ($K_i$). A lower value indicates tighter binding.

Distinguish between IC50 and EC50.

$IC_{50}$ is the concentration that inhibits a response by $50\%$ (used for antagonists), while $EC_{50}$ is the concentration producing $50\%$ of the maximal effect (used for agonists).

What are the concentration scales for nanomolar and micromolar, and which is generally required for drugs?

Nanomolar (nM) is $10^{-9}\,M$ (potent), and micromolar (\mu M) is $10^{-6}\,M$ (weak). Drugs generally must reach nM potency to be effective at feasible doses.

What is the formula for the dissociation constant $K_d$ in terms of kinetics?

$K_d = \frac{k_{off}}{k_{on}}$, where $k_{on}$ is the association rate and $k_{off}$ is the dissociation rate.

Define 'residence time' and its clinical significance.

Residence time is calculated as $1 / k_{off}$ and represents how long a drug stays bound. It can allow a drug to remain effective even after blood levels fall.

What does a selectivity of '\ge 100-fold' mean?

It means the molecule binds to its intended target at least $100$ times more tightly than it binds to an unintended off-target.

What is the 'selectivity window'?

The gap between the dose required to engage the intended target and the dose that begins to affect off-targets, where a wider window suggests better safety.

Identify the selectivity goals for IVL-THRB and IVL-5HT2B.

IVL-THRB targets $\ge 100$-fold selectivity for $TR\beta$ (liver) over $TR\alpha$ (heart). IVL-5HT2B targets $\ge 100$-fold selectivity for $5-HT_{2B}$ over $5-HT_{2A}$ and $5-HT_{2C}$.

Explain the mechanism and timescale of Nuclear Receptors (e.g., TR\beta).

They are ligand-activated transcription factors inside the cell that change gene transcription and protein levels. Their effect is slow, taking hours to days.

Explain the mechanism and timescale of GPCRs (e.g., 5-HT2B).

They relay outside signals to the cell interior via G proteins and second messengers (cAMP, calcium). Their effect is fast, taking seconds to minutes.

Why is the 5-HT2B receptor targeted for fibrosis therapy?

Because $5-HT_{2B}$ agonism is known to drive tissue fibrosis (seen in drugs like fen-phen), IVL's thesis is that antagonising it will be anti-fibrotic.

What are the two parts of the Ataxin-3 protein and which residue drives dimerization?

It consists of the Josephin domain (JD) and a C-terminal region with a polyglutamine (polyQ) tract. Dimerization is driven by residue Arg101.

What are the common trade-offs for the antibody (biologic) modality?

They are exquisitely specific but are limited to extracellular targets, cannot enter cells, are expensive, and must be injected.

State the four criteria of Lipinski's Rule of Five (Ro5).

Poor oral absorption is likely if: Molecular Weight $\le 500\,Da$, logP $\le 5$, Hydrogen-bond donors $\le 5$, and Hydrogen-bond acceptors $\le 10$.

What is the significance of TPSA and its threshold for the blood-brain barrier?

TPSA (topological polar surface area) is a proxy for membrane permeability; a value of $< \sim 90\,\text{\AA}^2$ is generally needed to cross the blood-brain barrier.