Medicinal Chemistry Lecture Review

Flashcards covering key concepts from medicinal chemistry including drug-receptor interactions, enzyme inhibition models, DNA-targeting agents, metabolic pathways, and Lipinski's rules.

Chirality (in receptor interactions)

A property where one enantiomer of a drug mixture may be responsible for therapeutic effects while the other causes unexpected toxicity.

Steric hindrance

The most likely explanation for when adding bulky groups during SAR optimization decreases a drug's activity at the binding pocket.

Partial agonist

A drug that competes for receptor occupancy but produces lower efficacy, acting as a functional antagonist in the presence of a full agonist.

Noncompetitive inhibition

A scenario where an inhibitor binds to an enzyme at a site distinct from the active site.

Inverse agonist

A drug that stabilizes the inactive receptor state to produce the opposite effect of an agonist.

Allosteric enzyme inhibitor

A drug that binds to a different binding site from the active site and affects the activity of the enzyme.

Binding site

A hollow or cleft on the surface of a drug target macromolecule that contains binding regions; it is not typically hydrophilic in nature.

Alkylating agent

A type of agent, such as Carmustine or Lomustine, used in multi-drug regimes for treating Hodgkin's lymphoma by adding alkyl groups to DNA.

Intercalating agents

Anticancer agents, like anthracyclines, that function by inserting between DNA base pairs and distorting the DNA structure.

Dipole-dipole interaction

An interaction most likely to occur with functional groups such as ketones.

Phospholipid bilayer

A cell membrane component made of two layers of phospholipids where water and ions cannot easily cross due to hydrophobic tails.

Split–mix (split–pool) method

A method primarily used in combinatorial chemistry to generate very large libraries of compounds.

Solid-phase synthesis

A method where the growing molecule is attached to an insoluble resin bead, often cleaved later by acidic or basic treatment.

Parallel synthesis

A synthesis method that differs from combinatorial synthesis by producing individual compounds in separate vessels.

Deconvolution

The process in combinatorial chemistry used to identify the active compound from a mixture.

Suicide inhibitor

A class of inhibitor that forms a covalent bond with the enzyme active site after initial binding and catalysis.

GPCR (G-Protein Coupled Receptor)

A receptor type that activates G-proteins leading to second messenger formation, such as increasing intracellular cAMP levels.

Tyrosine kinase receptor

A receptor that undergoes autophosphorylation on tyrosine residues when activated by ligand binding.

Transcription

The biological process of converting DNA into RNA.

Translation

The biological process of converting RNA into proteins, which can be blocked by antisense binding.

Induced-fit model

An enzyme model suggesting that the enzyme undergoes a conformational change (changes shape) upon substrate binding.

Lock-and-key model

A model of enzyme action that assumes a rigid active site.

Alpha-helix

A level of secondary protein structure characterized by intramolecular hydrogen bonding.

Beta-sheet

A secondary protein structure primarily stabilized by hydrogen bonds.

Ion channel receptor

A fast-responding receptor that allows ion flow across membranes, such as opening sodium channels to cause rapid depolarization.

Intracellular receptor

A receptor type typically activated by lipophilic ligands, such as steroid hormones, which can alter gene expression.

Topoisomerase inhibitors

Drugs that inhibit DNA replication by preventing DNA unwinding.

Cytochrome P450

A major enzyme system responsible for Phase I oxidative metabolism (like aromatic hydroxylation) and common drug–drug interactions.

Prodrug

An inactive compound used to improve absorption or stability that is converted into the active drug in vivo.

Bioisosteric replacement

A strategy used to retain activity while modifying properties such as potency or metabolic stability (e.g., replacing a methyl with trifluoromethyl).

Lipinski’s Rule of Five

Guidelines to estimate oral absorption likelihood: MW $\le 500$, HBD $\le 5$, HBA $\le 10$, and $logP \le 5$.

LogP

A parameter reflecting the balance between hydrophilicity and lipophilicity; it represents the partitioning of a neutral drug between octanol and water.

Polar Surface Area (PSA)

A physical property where high values usually lead to poor membrane permeability.

Molecular docking

A computational method used to predict ligand–protein interactions and the 3D orientation (binding pose) of a ligand in a binding site.

Docking score

A numerical value (e.g., $-9.5 \, \text{kcal/mol}$) where a more negative score generally indicates stronger binding affinity.

Ligand efficiency

The binding energy of a ligand per atom or size unit.

Virtual screening

A computational technique used to identify potential drug candidates from large libraries.

Molecular dynamics simulations

Simulations used to study the time-dependent behavior of molecules.

Phase II metabolism

Metabolic reactions involving conjugation, such as glucuronidation, which increases water solubility and excretion.