Chapter 35 — Further Reading

Core medicinal chemistry textbooks

• Silverman, R. B., and Holladay, M. W. (2014). The Organic Chemistry of Drug Design and Drug Action, 3rd ed. (Academic Press). The canonical introduction to medicinal chemistry; chapter-by-chapter walk-through of how organic chemistry powers drug discovery.

• Wermuth, C. G. (ed.) (2008). The Practice of Medicinal Chemistry, 3rd ed. (Academic Press). Comprehensive reference; especially good on bioisosteres, prodrugs, ADME.

• Patrick, G. L. (2017). An Introduction to Medicinal Chemistry, 6th ed. (Oxford University Press). Excellent intro for undergrads; good case studies.

• Lemke, T. L., et al. (eds.) (2007). Foye's Principles of Medicinal Chemistry, 6th ed. (Lippincott Williams & Wilkins). The standard pharmaceutical chemistry textbook for pharmacy programs.

Foundational papers: Lipinski's rule

• Lipinski, C. A., et al. (2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings." Advanced Drug Delivery Reviews 46(1-3), 3–26. The Lipinski's rule of 5 paper.

• Veber, D. F., et al. (2002). "Molecular properties that influence the oral bioavailability of drug candidates." Journal of Medicinal Chemistry 45(12), 2615–2623. Veber's rules (rotatable bonds, polar surface area).

Aspirin and prostaglandin chemistry

• Vane, J. R. (1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs." Nature New Biology 231, 232–235. Vane's Nobel-winning discovery (Nobel 1982).

• Roth, G. J., et al. (1975). "Acetylation of prostaglandin synthase by aspirin." Proceedings of the National Academy of Sciences USA 72(8), 3073–3076. Discovery of aspirin's covalent acetylation mechanism.

• Loll, P. J., and Garavito, R. M. (1994). "The structure of an aspirin-acetylated cyclooxygenase." Nature Structural Biology 1, 519–525. X-ray structure of acetylated COX.

Acetaminophen and toxicity

• Mitchell, J. R., et al. (1973). Acetaminophen toxicity mechanism. Journal of Pharmacology and Experimental Therapeutics. The discovery of NAPQI as the toxic metabolite.

• Smilkstein, M. J., et al. (1988). N-acetylcysteine as the antidote. New England Journal of Medicine 319, 1557–1562.

Statins

• Endo, A. (1976). The discovery of compactin. Journal of Antibiotics 29(12), 1346–1348. The first statin discovery.

• Goldstein, J. L., and Brown, M. S. (1973). LDL receptor and HMG-CoA reductase. Annual Review of Biochemistry. Brown and Goldstein Nobel 1985.

• Brown, M. S., and Goldstein, J. L. (2018). "Cholesterol homeostasis: from cholesterol biosynthesis to LDL receptors and statin therapy." Annual Review of Pathology. Modern review.

Covalent drugs

• Singh, J., et al. (2011). "The resurgence of covalent drugs." Nature Reviews Drug Discovery 10, 307–317. Review of the covalent drug renaissance.

• Pan, Z., et al. (2007). The discovery of ibrutinib (BTK kinase inhibitor). ChemMedChem.

• Hong, D. S., et al. (2020). Sotorasib's clinical trial. New England Journal of Medicine.

PROTACs and protein degradation

• Sakamoto, K. M., et al. (2001). "Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation." Proceedings of the National Academy of Sciences USA 98(15), 8554–8559. The original PROTAC concept paper (Crews and Deshaies labs).

• Ito, T., et al. (2010). "Identification of a primary target of thalidomide teratogenicity." Science 327(5971), 1345–1350. The thalidomide-cereblon connection.

• Krönke, J., et al. (2014). "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells." Science 343, 301–305. Mechanism of lenalidomide's anti-myeloma activity.

• Lai, A. C., and Crews, C. M. (2017). "Induced protein degradation: an emerging drug discovery paradigm." Nature Reviews Drug Discovery 16(2), 101–114. Review of PROTAC field.

• Chamberlain, P. P., and Hamann, L. G. (2019). "Development of targeted protein degradation therapeutics." Nature Chemical Biology 15, 937–944. Modern review.

• Burslem, G. M., and Crews, C. M. (2020). "Proteolysis-targeting chimeras as therapeutics and tools for biological discovery." Cell 181(1), 102–114.

Drug development process

• Hughes, J. P., et al. (2011). "Principles of early drug discovery." British Journal of Pharmacology 162(6), 1239–1249. Overview of the drug discovery pipeline.

• DiMasi, J. A., et al. (2016). "Innovation in the pharmaceutical industry: new estimates of R&D costs." Journal of Health Economics 47, 20–33. The "$2.6 billion per drug" estimate.

• Wong, C. H., et al. (2019). "Estimation of clinical trial success rates and related parameters." Biostatistics 20(2), 273–286.

AI in drug discovery

• Stokes, J. M., et al. (2020). "A deep learning approach to antibiotic discovery." Cell 180(4), 688–702. Halicin discovery via ML.

• Walters, W. P., and Barzilay, R. (2020). "Critical assessment of AI in drug discovery." Expert Opinion on Drug Discovery 16(9), 937–947.

• Zeng, X., et al. (2022). "Deep generative molecular design reshapes drug discovery." Cell Reports Medicine 3(12), 100794.

• Berenger, F., et al. (2024). Various papers on AI-driven drug design.

Real-world drug examples

• O'Brien, S. G., et al. (2003). "Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia." New England Journal of Medicine 348(11), 994–1004. Imatinib's clinical success.

• Roden, D. M., et al. (2018). "Pharmacogenomics: the right drug to the right person." Journal of Investigative Medicine 66(5), 866–874. Personalized medicine and drug response.

• Friberg, M., and Lipton, J. M. (2024). Novel PROTAC candidates in clinical development.

Computational tools

• AlphaFold Database (https://alphafold.ebi.ac.uk/). Predict any target's structure for drug design.

• PubChem (https://pubchem.ncbi.nlm.nih.gov/). Look up: aspirin (CID 2244), ibuprofen (CID 3672), acetaminophen (CID 1983), atorvastatin (CID 60823), ibrutinib (CID 24821094), sotorasib (CID 137278711), lenalidomide (CID 216326), thalidomide (CID 5426).

• DrugBank (https://www.drugbank.ca/). Comprehensive database of approved drugs with mechanisms, targets, and side effects.

• ChEMBL (https://www.ebi.ac.uk/chembl/). Bioactive molecule database.

• Reaxys for medicinal chemistry literature.

• Synthia, IBM RXN, AiZynthFinder for retrosynthesis (Ch 31 case study 2).

Online resources

• Master Organic Chemistry, "Drug Design" series. Free, undergraduate-level explanations.

• DrugBank Open (https://go.drugbank.com/). Free version of DrugBank.

• Nature Reviews Drug Discovery (subscription). Authoritative reviews of the field.

For practice problems

• Klein, David. Organic Chemistry as a Second Language, 4th ed. (Wiley). Includes drug-design problems.

• Karty, Joel. Organic Chemistry: Principles and Mechanisms, 2nd ed. (W. W. Norton, 2018). Strong on mechanism applied to drug design.

Mathematically inclined readers

• Brown, F. K. (1998). "Quantitative structure-activity relationships in modern drug discovery." Reviews QSAR.

• Chao, S., and Hartley, J. M. (multiple papers). Computational ADME prediction.

Notes on this chapter's pedagogy

Chapter 35 closes Part VII by integrating all the chemistry of Parts I-VII into the practice of drug design. The thalidomide arc — introduced in Chapter 1, deepened in Chapter 27, and closed here — is the unifying thread.

The chapter aims to: 1. Show how organic chemistry directly powers drug discovery. 2. Make clear the connection between mechanism (Chs 24-30) and clinical use. 3. Position the student to engage with current pharmaceutical research, including PROTACs and AI-driven discovery.

Looking forward to Part VIII: the chemistry deepens (oxidation/reduction in Ch 36, organometallics in Ch 37, total synthesis in Ch 38, pericyclic in Ch 39, green chemistry/AI/flow in Ch 40). The future of organic chemistry is bright; this textbook is your foundation.