CabinetTour

Caffeine

Binds the adenosine A2A receptor: Adenosine receptor A2a, Homo sapiens · UniProt P29274

Caffeine binds in the pocket of the adenosine A2A receptor where adenosine itself binds, so adenosine cannot bind there.

Two lines of history

• Caffeine's main effect in the brain comes from blocking adenosine receptors. Fredholm et al. 1999, Actions of caffeine in the brain with special reference to factors that contribute to its widespread use (Pharmacol Rev)
• A 2011 crystal structure showed caffeine in the A2A receptor's adenosine pocket. Doré et al. 2011, Structure of the adenosine A2A receptor in complex with ZM241385 and the xanthines XAC and caffeine (Structure)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Ibuprofen

Binds a cyclooxygenase (COX) enzyme: Prostaglandin G/H synthase 2, Mus musculus · UniProt Q05769

Ibuprofen sits in the long channel of a COX enzyme, blocking the active site so the enzyme cannot make prostaglandins.

No deposited structure holds this medicine in the UniProt P35354 or UniProt P23219 proteins looked up first (human), so this card shows the same kind of enzyme from the organism where one exists.

Two lines of history

• Ibuprofen came out of work on new pain-relieving acids by Stewart Adams and colleagues at Boots in the 1960s. Adams 1992, The propionic acids: a personal perspective (J Clin Pharmacol)
• In 1971 John Vane showed that aspirin-like drugs stop cells making prostaglandins. Vane 1971, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs (Nature New Biol)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Aspirin

Binds a cyclooxygenase (COX) enzyme: Prostaglandin G/H synthase 1, Homo sapiens · UniProt P23219

Aspirin hands an acetyl group to a serine in the COX active site. The acetyl blocks the channel, and the enzyme stays blocked.

Two lines of history

• In 1971 John Vane showed that aspirin stops cells making prostaglandins. Vane 1971, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs (Nature New Biol)
• In 1975 Roth, Stanford and Majerus showed that aspirin acetylates the enzyme that makes prostaglandins. Roth, Stanford & Majerus 1975, Acetylation of prostaglandin synthase by aspirin (PNAS)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Penicillin

Binds a penicillin-binding protein of a bacterium: D-alanyl-D-alanine carboxypeptidase DacB, Escherichia coli (strain K12) · UniProt P24228

Penicillin bonds to the active-site serine of penicillin-binding proteins, the enzymes that build a bacterium's cell wall, and blocks them.

Two lines of history

• In 1928 Alexander Fleming noticed that a Penicillium mould stopped bacteria growing around it, and published it in 1929. Fleming 1929, On the antibacterial action of cultures of a penicillium (Br J Exp Pathol)
• In 1965 Tipper and Strominger proposed that penicillin works by looking like the end of a cell-wall building block. Tipper & Strominger 1965, Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-D-alanyl-D-alanine (PNAS)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

A statin (atorvastatin)

Binds HMG-CoA reductase: 3-hydroxy-3-methylglutaryl-coenzyme A reductase, Homo sapiens · UniProt P04035

Atorvastatin binds in the active site of HMG-CoA reductase, the enzyme that makes an early step on the way to cholesterol, and blocks it.

Two lines of history

• In 1976 Akira Endo and colleagues reported the first statin, found in a Penicillium mould. Endo, Kuroda & Tsujita 1976, ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum (J Antibiot)
• Statins share part of their shape with the enzyme's own starting molecule, HMG-CoA, and fill the pocket where it binds. Istvan & Deisenhofer 2001, Structural mechanism for statin inhibition of HMG-CoA reductase (Science)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

An antihistamine (desloratadine)

Binds the histamine H1 receptor: Histamine H1 receptor, Homo sapiens · UniProt P35367

Desloratadine binds in the pocket of the histamine H1 receptor where histamine binds, so histamine cannot switch the receptor on.

Two lines of history

• Daniel Bovet's work in the 1930s led to the first antihistamines; he received the 1957 Nobel Prize. The Nobel Prize in Physiology or Medicine 1957, Daniel Bovet
• The Seen structure was reported by Wang et al., 2024, Nat Commun (paper).

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Omeprazole

Binds the stomach's proton pump (H+/K+ ATPase): Potassium-transporting ATPase alpha chain 1, Homo sapiens · UniProt P20648

In acid, omeprazole turns into a form that bonds to cysteines on the outside of the stomach's proton pump and blocks it.

Two lines of history

• Omeprazole, the first proton-pump inhibitor, came out of research at Astra Hässle in Sweden. Olbe, Carlsson & Lindberg 2003, A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole (Nat Rev Drug Discov)
• The pill is not the active form: the change happens in acid, next to the pump. Olbe, Carlsson & Lindberg 2003, A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole (Nat Rev Drug Discov)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Insulin

Binds insulin itself: Insulin, Homo sapiens · UniProt P01308

Insulin is itself a small protein, two chains joined by sulphur bridges. It binds the insulin receptor on the outside of cells.

Two lines of history

• In Toronto in 1921 and 1922, Banting, Best, Collip and Macleod first purified insulin; Banting and Macleod received the 1923 Nobel Prize. The Nobel Prize in Physiology or Medicine 1923, Banting and Macleod
• In 1969 Dorothy Hodgkin's group solved the 3D structure of insulin. Adams et al. 1969, Structure of rhombohedral 2 zinc insulin crystals (Nature)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

A GLP-1 medicine (semaglutide)

Binds the GLP-1 receptor: Glucagon-like peptide 1 receptor, Homo sapiens · UniProt P43220

Semaglutide is a modified copy of the gut hormone GLP-1. It binds the GLP-1 receptor where GLP-1 binds and switches it on.

Two lines of history

• Semaglutide carries a fatty side chain that lets it ride on albumin in the blood, so it lasts far longer than GLP-1. Lau et al. 2015, Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide (J Med Chem)
• The Seen structure was reported by Zhang et al., 2021, Cell Rep (paper).

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

An ACE inhibitor (lisinopril)

Binds angiotensin-converting enzyme (ACE): Angiotensin-converting enzyme, Homo sapiens · UniProt P12821

Lisinopril binds in the active site of ACE, next to its zinc atom, and blocks the enzyme.

Two lines of history

• The first ACE inhibitors grew out of peptides found in the venom of a Brazilian pit viper, Bothrops jararaca; captopril was designed from them in the 1970s. Ondetti, Rubin & Cushman 1977, Design of specific inhibitors of angiotensin-converting enzyme (Science)
• The Seen structure was reported by Natesh et al., 2003, Nature (paper).

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Oseltamivir

Binds influenza neuraminidase: Neuraminidase, Influenza A virus (strain A/Vietnam/1203/2004 H5N1) · UniProt Q6DPL2

Oseltamivir carboxylate binds in the active site of the flu virus's neuraminidase and blocks it.

Two lines of history

• Oseltamivir was designed in the 1990s from the shape of the neuraminidase active site. Kim et al. 1997, Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site (J Am Chem Soc)
• The capsule holds an ethyl ester; the body turns it into the active carboxylate. Kim et al. 1997, Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site (J Am Chem Soc)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.

Imatinib

Binds the ABL kinase: Tyrosine-protein kinase ABL1, Homo sapiens · UniProt P00519

Imatinib binds in the ATP pocket of the ABL kinase, so ATP cannot bind there and the kinase is blocked.

Two lines of history

• In 1996 Druker and colleagues showed that a selective ABL kinase blocker (later named imatinib) stopped the growth of Bcr-Abl cells. Druker et al. 1996, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells (Nat Med)
• Imatinib is one of the best-known examples of a medicine designed to block one kinase. Druker et al. 1996, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells (Nat Med)

Nothing here is advice about taking any medicine: no doses, no conditions, nothing stored.