Med Chem Unit 5

What are the four primary types of proteins that serve as drug targets?

Enzymes, receptors, transport proteins, and ion channels.

Beyond proteins, what are the two main types of nucleic acid drug targets?

DNA and RNA.

The specific region on a drug target where a molecule physically attaches to produce a biological effect is called the _____.

Binding site (or binding pocket).

Which model proposes that an enzyme's active site has a fixed, rigid shape that exactly complements the substrate?

Lock and Key Model.

Which model, proposed by Daniel Koshland, suggests enzymes undergo conformational changes to stabilize a substrate upon binding?

Induced Fit Model.

What is the typical bond strength range for covalent drug-target interactions?

$40-150$ kcal/mol.

Why are covalent drug-target interactions generally considered irreversible?

The high bond strength requires metabolic turnover or cellular replenishment of the target protein to terminate the effect.

What are the five common mechanisms by which drugs form covalent bonds with their targets?

Alkylation, metalation, acylation, phosphorylation, and rearrangement.

Term: Alkylating agents

Definition: Highly electrophilic compounds that react with nucleophilic groups on DNA or other targets to form stable covalent bonds.

Name three examples of nitrogen mustard alkylating agents.

Chlormethine, melphalan, and estramustine.

Cyclophosphamide is an example of which type of covalent bonding agent?

Phosphoramide mustard (alkylating agent).

Term: Nucleophilic group

Definition: An atom or functional group that donates an electron pair to form a new covalent bond.

Term: Electrophilic group

Definition: An atom or functional group that accepts an electron pair to form a new covalent bond.

A metal-ligand interaction where a ligand donates an electron pair to a metal ion is called a _____ bond.

Dative (or coordinate covalent) bond.

In a coordinate covalent bond, the metal ion acts as a Lewis _____.

Acid (electron-pair acceptor).

Which type of covalent interaction occurs when a nucleophilic target atom attacks an ester, lactone, or lactam group in a drug?

Acylation.

Identify three functional groups in drugs that are commonly susceptible to acylation by biological targets.

Esters, amides, and $\beta$-lactams.

By what mechanism does Aspirin interact with its target?

Acylation.

$\beta$-Lactam antibiotics inhibit the bacterial enzyme _____ to prevent cell wall cross-linking.

Transpeptidase.

The inhibition of transpeptidase by $\beta$-lactams involves the formation of a covalent _____ bond.

Acyl.

What is the primary difference between covalent and noncovalent interactions regarding electrons?

Covalent interactions involve sharing electrons, while noncovalent interactions do not.

Which noncovalent interaction involves a charged ionic group interacting with a permanent dipole in another molecule?

Ion-dipole interaction.

The ability to form an ion-dipole bond is proportional to _____.

$1/r^2$ (where $r$ is the distance between groups).

The interaction between the ionized amine of atomoxetine and a phenylalanine residue is an example of a _____ interaction.

Cation-$\pi$.

Term: Charge transfer interaction

Definition: An interaction where electron density is partially transferred from an electron-rich aromatic ring to an electron-deficient aromatic ring via overlapping $\pi$ orbitals.

What is the structural requirement for a charge transfer interaction?

The presence of an electron donor (rich ring) and an electron acceptor (deficient ring).

Chelation occurs when a metal ion binds to a molecule through _____ or more donor atoms.

Two.

What is the characteristic structural result of a chelation interaction?

The formation of a stable ring-like complex.

How does metal complexation differ from chelation?

Complexation involves interaction with a single donor atom or functional group without forming a ring structure.

Which metal ion does Enalaprilat interact with at its binding site?

$Zn^{2+}$ (Zinc).

Ciprofloxacin interacts with which metal ion via chelation?

$Ca^{2+}$ (Calcium).

Tetracycline interacts with bacterial ribosomes by binding to which metal ion?

$Mg^{2+}$ (Magnesium).

Term: Stereochemistry

Definition: The study of the three-dimensional arrangement of atoms in molecules and its effect on chemical properties and biological activity.

Stereoisomers that are non-superimposable mirror images of each other are called _____.

Enantiomers.

In the enantiomeric pair of Albuterol, which isomer is responsible for beneficial bronchodilation?

$R-(-)$-Albuterol.

Which isomer of Albuterol is associated with adverse effects?

$S-(+)$-Albuterol.

Term: Diastereoisomers

Definition: Stereoisomers that have the same sequence of atoms but are not mirror images of each other.

True or False: Enantiomers usually have different physical properties like melting points and solubility.

False (Diastereoisomers have different physical properties; enantiomers have identical physical properties in achiral environments).

Which type of isomerism results from rotation around a single rotatable bond?

Conformational isomerism.

The specific conformation of a molecule that binds productively to its biological target is the _____ conformation.

Active.

Why might a medicinal chemist restrict the flexibility of a drug molecule?

To lock it into its active conformation, increasing potency and selectivity while reducing entropic penalties.

Term: Structure-Activity Relationship (SAR)

Definition: The relationship between the chemical structure of a molecule and its biological activity.

In drug discovery, a molecule that displays desired activity in a screening assay is called a _____.

Hit compound.

Term: Lead compound

Definition: A promising molecule derived from hits that shows desired pharmacological activity and serves as a starting point for optimization.

What is the goal of hit-to-lead optimization?

Refining a hit compound into a potential drug candidate (lead) with improved properties.

Term: Pharmacophore

Definition: A combination of steric and electronic features necessary to ensure optimal interactions with a biological target and trigger its response.

Name the four components of the morphine pharmacophore.

A benzene ring, a quaternary carbon, a two-carbon spacer, and a tertiary amine.

What four properties can be improved by the strategic introduction of Fluorine into a drug molecule?

Metabolic stability, lipophilicity, potency/selectivity, and conformation.

How does Fluorine improve metabolic stability?

The strong $C-F$ bond can block metabolic "soft spots" by resisting oxidative cleavage.

Term: Homologation

Definition: The process of increasing or decreasing the carbon chain length (chain extension/contraction) in a series of analogs.

List three purposes of molecular modification through homologation.

Probing target steric dimensions, increasing lipid solubility, and optimizing target-site interactions.

The addition of double bonds to a molecule increases its _____.

Rigidity.

How did the introduction of a double bond affect the activity of cortisol?

It led to a 4-fold increase in anti-inflammatory activity.

What is the primary objective of using a prodrug strategy?

To improve solubility, gastrointestinal stability, or delivery of the parent compound.

Who first defined isosteres in 1919 as groups with the same number and arrangement of electrons?

Irving Langmuir.

According to Grimm's Hydride Displacement Law, the addition of a _____ to an atom results in a pseudoatom.

Hydride ($H$).

Using Grimm's Law, what pseudoatom is produced by adding a hydride to a Carbon ($C$) atom?

$CH$.

Term: Bioisosteres

Definition: Substituents or groups that have chemical or physical similarities and produce similar biological effects when incorporated into a drug.

Beyond optimizing potency and ADME, why do scientists use bioisosteric replacement?

To strengthen intellectual property and secure patent protection.

What effect does adding a bulky group have on $\beta$-lactam drugs regarding resistance?

It creates steric hindrance that protects the $\beta$-lactam ring from hydrolysis by $\beta$-lactamases.

Epinephrine is unique because it activates both _____ and _____ adrenergic receptors.

$\alpha$; $\beta$.

Which historical figures first presented the idea of linking chemical structure to biological activity in 1868?

Alexander Crum Brown and Thomas Richard Fraser.

The ability of a negative charge to be shared across oxygen atoms in a carboxylic acid is due to _____.

Resonance.

How does resonance affect functional groups in drug-target binding?

It enhances the acidity or basicity of specific groups by allowing charges to be shared among multiple atoms.

A stable conformation where two groups have a dihedral angle of $60^{\circ}$ can be represented using which two types of diagrams?

Sawhorse and Newman diagrams.

In drug discovery, the multidisciplinary collaboration usually requires which two types of professionals?

Chemists (Medicinal Chemists) and Biologists.

The term "hydrophilic" literally translates to _____.

Water loving.

The term "lipophilic" literally translates to _____.

Fat loving.

What is the significance of ADME in SAR studies?

It describes the physicochemical properties that influence how a drug is absorbed, distributed, metabolized, and excreted.

What distinguishes the $S1$ and $S1'$ pockets in the binding site of Enalaprilat?

They are distinct hydrophobic sub-pockets that accommodate different parts of the drug molecule.

Isomer pair identification: $(S,R)$-trans epoxide vs $(S,S)$-cis epoxide are examples of _____.

Diastereoisomers.

The design of raltegravir utilizes its ability to act as a _____ chelator.

Metal ion.

Which functional group in raltegravir is specifically circled as a metal-binding system?

Diketo-enol system.

True or False: The preferred (lowest energy) conformation of a drug is always the active conformation.

False (The active conformation is the one that binds to the target, which may require higher energy than the preferred state).

Approximately how many years and what cost are associated with getting a new drug to the clinic?

$10-15$ years and roughly $\$2$ billion.

Identify the type of noncovalent interaction: Interaction between an electron-deficient ring and an electron-rich tryptophan residue.

Charge transfer interaction.

What specific bacterial enzyme is inhibited by Penicillin to stop cell wall synthesis?

Penicillin-binding proteins (PBPs), specifically transpeptidases.

How does the size of a ring (e.g., $6,5,6$ vs $6,7,6$) affect drug activity in a binding site?

It changes the spatial arrangement of hydrophobic groups, determining if they align optimally with hydrophobic binding regions.

What is the role of a "warhead" in a covalent inhibitor?

It is the reactive functional group that forms the irreversible covalent bond with the protein target.

The process of refining a lead compound to enhance safety and efficacy is known as _____.

Lead optimization.