Chapter 35 — Exercises

Fifty-five problems on drug design, mechanism, and medicinal chemistry. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Aspirin, ibuprofen, acetaminophen mechanisms

35.1∗ (routine) Explain aspirin's mechanism using Ch 26 nucleophilic acyl substitution. Identify the nucleophile, electrophile, and leaving group in COX inhibition.

35.2 (routine) Why is aspirin's inhibition of COX irreversible while ibuprofen's is reversible? Explain the chemical basis.

35.3∗ (routine) Predict whether (R)- or (S)-ibuprofen is the active enantiomer for COX inhibition. Connect to Ch 7 stereochemistry.

35.4 (routine) A pharmacy bottle says "Take ibuprofen with food." Why? Mechanism of GI side effects.

35.5 (moderate) Aspirin's effect on platelet COX lasts ~10 days, while ibuprofen's effect lasts only the duration of plasma drug. Why is the difference clinically significant?

35.6 (moderate) Why does acetaminophen overdose cause liver damage? Mechanism: CYP2E1 → NAPQI → Michael acceptor → glutathione depletion → cysteine modification.

35.7 (challenge) Draw the mechanism of NAPQI's Michael addition to glutathione. Identify the nucleophile, the α,β-unsaturated electrophile, and the new C-S bond.

35.8 (challenge) Why does N-acetylcysteine (NAC) reverse acetaminophen toxicity if given within ~10 hours? What is its mechanism?

Section B — Lipinski's rule of 5

35.9∗ (routine) Apply Lipinski's rule of 5 to: (a) Aspirin (MW 180; logP ~1.2; H-bond donors 1; H-bond acceptors 4) (b) Ibuprofen (MW 206; logP 3.5; H-bond donors 1; H-bond acceptors 2) (c) Acetaminophen (MW 151; logP 0.5; H-bond donors 2; H-bond acceptors 3) (d) Atorvastatin (MW 558; logP 5.7; H-bond donors 4; H-bond acceptors 6) Are each drug-like by Lipinski's criteria?

35.10 (routine) Why is high logP (>5) bad for oral absorption? Why is too low logP (<1) also bad?

35.11 (moderate) A peptide drug has MW > 1000. Can it be orally absorbed? Why do most peptide drugs require injection?

35.12 (moderate) Beyond Lipinski's rule of 5, Veber's rules add: rotatable bonds ≤ 10; polar surface area ≤ 140 Ų. Why are these added criteria important?

35.13 (challenge) A "CNS drug" has additional design constraints (BBB crossing). What are the typical rules? Why are they tighter than Lipinski's?

Section C — SAR (Structure-Activity Relationships)

35.14∗ (routine) Outline an SAR table for hypothetical hit compound. Show: lead, lead + methyl, lead + fluorine, lead with smaller ring, lead with larger ring. Predict which modifications would be useful.

35.15 (routine) When optimizing a lead, what is the typical order of priorities: potency, then selectivity, then ADME?

35.16 (moderate) Why is fluorine such a popular substituent in medicinal chemistry?

35.17 (moderate) Why are tert-butyl groups often added to drug candidates to improve metabolic stability?

35.18 (challenge) A lead compound has IC₅₀ = 1 μM at the target but also at 5 off-targets. How does the chemist optimize for selectivity?

Section D — Bioisosteres

35.19∗ (routine) Match each functional group to its common bioisostere: (a) -COOH → ___ (b) -OH → ___ (c) -CH₂- in chain → ___ (d) phenyl → ___

35.20 (routine) Why might you swap an ester (-COOR) for an amide (-CONHR) in a drug structure? What property changes?

35.21 (moderate) Swap the -COOH of a drug for a tetrazole. Sketch the structure. Why is this often beneficial?

35.22 (moderate) Replace -OH with -CF₃ in a drug. Predict the consequences for: H-bonding, lipophilicity, metabolism, and target binding.

35.23 (challenge) A drug contains a -CONH- amide bond between two parts of the molecule. The drug is rapidly cleaved by aminopeptidases. Suggest a bioisosteric replacement.

Section E — Prodrugs

35.24∗ (routine) Identify the prodrug-active drug pair: (a) Enalapril → ___ (active metabolite) (b) Valacyclovir → ___ (c) L-DOPA → ___ (across BBB, then activated)

35.25 (routine) Why is enalapril a prodrug rather than just enalaprilat? What does the ester strategy accomplish?

35.26 (moderate) Design a prodrug of a hypothetical drug with a free -COOH. The drug has poor oral bioavailability due to the polar carboxylic acid. Suggest an ester prodrug strategy and the expected metabolism.

35.27 (moderate) Some antibiotics (e.g., cefuroxime axetil) are prodrugs cleaved in the gut wall during absorption. What is the chemistry? Why is this clinically useful?

35.28 (challenge) L-DOPA is a prodrug for dopamine in the brain. Why is dopamine itself not given (despite being the active form)? Why is carbidopa added?

Section F — Pharmacokinetics and Pharmacodynamics

35.29∗ (routine) Define ADME (absorption, distribution, metabolism, excretion). For each, what kind of chemistry/property is involved?

35.30 (routine) Why does CYP3A4 metabolize so many drugs? Connect to its broad substrate specificity.

35.31 (moderate) Drug-drug interactions via CYP3A4 inhibition: a common cause of clinical problems. Give an example.

35.32 (moderate) Half-life of a drug determines dosing frequency. A drug with t₁/₂ = 24 hr can be dosed once daily. What about t₁/₂ = 4 hr? t₁/₂ = 7 days?

35.33 (challenge) Why do drugs that bind membrane proteins (receptors) need to cross cell membranes (or at least be at the cell surface)? Connect to logP and Lipinski.

Section G — Covalent inhibitors and selective drugs

35.34∗ (routine) Identify covalent inhibitors among: (a) Aspirin (b) Ibrutinib (BTK kinase inhibitor) (c) Lenalidomide (d) Sotorasib (K-Ras G12C)

35.35 (routine) Why are covalent inhibitors having a renaissance in 2010s-2020s? What design principles make them work?

35.36 (moderate) Sketch the structure of an acrylamide warhead. Why is this the most common covalent warhead in cysteine-targeting drugs?

35.37 (moderate) Sotorasib targets specifically K-Ras G12C (a mutation introducing a cysteine at position 12). Why is this a uniquely druggable mutation?

35.38 (challenge) Compare aspirin's ester warhead (acetyl transfer to serine) with ibrutinib's acrylamide warhead (Michael addition to cysteine). What chemistry is involved in each?

Section H — PROTACs (the thalidomide comeback)

35.39∗ (routine) What is a PROTAC? Identify the three components: target ligand, linker, E3 ligase ligand.

35.40 (routine) Sketch a generic PROTAC with thalidomide as the cereblon-binding ligand. Why thalidomide?

35.41 (moderate) A PROTAC works catalytically: one molecule degrades many targets. Why? Connect to ternary complex chemistry.

35.42 (moderate) A common PROTAC failure mode is the "hook effect": too much PROTAC reduces activity. Why? What does this say about ternary complex formation?

35.43 (challenge) Design a PROTAC for a hypothetical kinase target. Identify: (a) the cereblon-binding ligand (e.g., thalidomide derivative), (b) the kinase-binding ligand (e.g., ATP-competitive inhibitor), (c) the linker (length, composition).

35.44 (challenge) Beyond cereblon, other E3 ligases (VHL, IAP, MDM2) can be used in PROTACs. Why might you choose one over another? Connect to tissue distribution and substrate specificity.

Section I — Drug design strategies

35.45∗ (routine) Compare: (a) High-throughput screening (HTS). (b) Fragment-based drug discovery (FBDD). (c) Structure-based drug design. (d) AI-driven virtual screening. What are the strengths and limitations of each?

35.46 (routine) Why are crystal structures of target proteins so important for drug design?

35.47 (moderate) A drug candidate has IC₅₀ = 100 nM in vitro but is inactive in cells. What chemistry might be wrong? List 3 possibilities.

35.48 (challenge) Design a drug-discovery campaign for a novel cancer target. What steps do you take? What chemistry do you apply at each step?

Section J — Looking forward

35.49 (routine) What are the five main classes of drugs currently in development? Examples: small molecules, biologics, peptides, oligonucleotides, cell/gene therapies.

35.50 (moderate) AI-driven drug discovery (Recursion, Insitro, Atomwise, etc.) is accelerating. What chemistry tasks does AI help with? What does it not yet do?

35.51 (moderate) A 2024 trend: targeted protein degradation (PROTACs, molecular glues, IKK inhibitors). Why is this such an active field?

35.52 (challenge) Outline a hypothetical "drug of the future" — using AI design + targeted degradation + cell-specific delivery. What chemistry is needed?

Section K — Integrative

35.53∗ (routine) Trace the chemistry of aspirin from 1900 (synthesis from salicylic acid + acetic anhydride) to 2025 (cardiovascular prevention drug; covalent COX inhibitor). Identify the chapters of this textbook involved.

35.54 (challenge) A complete drug-design exercise: take a known disease (e.g., Alzheimer's), identify a druggable target (e.g., BACE1), and outline a drug-discovery campaign using Chapters 1-35.

35.55 (challenge) Draw the connection between the chemistry of Chapters 24-30 (carbonyls), 32-34 (biology), and 35 (drugs). How does each element of Part VI feed into the rational design of medicines?

Notes for instructors: Common stumbling blocks for Chapter 35: (1) Confusing aspirin's covalent mechanism with ibuprofen's reversible mechanism. (2) Forgetting the chemistry of NAPQI as a Michael acceptor. (3) Misidentifying the active enantiomer of a chiral drug. (4) Failing to apply Lipinski's rule correctly. Computational exercises: use AlphaFold to predict the structure of a target protein and dock a known drug; compare to experimental data.