Medicinal Chemistry · Short notes

Drug Design Principles: Short Notes & Cheat Sheet

The discovery pipeline, lead compounds, drug–receptor bonding, lead optimisation, computer-aided design and chiral switches.

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Short notes

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From target to medicine

Most candidates fail on the way. Only a small fraction of compounds entering clinical trials is ever approved.

Finding a lead

A lead compound shows the wanted activity but needs improving. Leads come from natural products (morphine, penicillin, artemisinin, paclitaxel), chance discoveries, side effects of existing drugs, and screening.
Serendipity: penicillin (Fleming), chlordiazepoxide, sildenafil (developed for angina) and minoxidil (hair growth noticed as a side effect).
High-throughput screening tests thousands of compounds quickly; fragment-based design grows small binding fragments into leads.
Rational design uses knowledge of the target: captopril was designed from snake-venom peptides and the structure of ACE; cimetidine from histamine; HIV protease inhibitors and imatinib from target structures.

How drugs bind

Bond strength, strongest first: covalent > ionic > hydrogen bond > dipole interactions > van der Waals (hydrophobic).
Covalent binding is usually irreversible: aspirin (acetylates COX), penicillins (acylate PBPs), phenoxybenzamine, omeprazole and organophosphates.
Most drugs bind reversibly through several weaker bonds, so their effect ends as concentration falls.
The Easson–Stedman hypothesis: a chiral drug needs a three-point fit, which is why enantiomers can differ in activity.

Optimising the lead

Strategies: vary substituents, extend or shorten chains (homologation), change or fuse rings, simplify the structure, and rigidify it (conformational restriction) to lock in the active shape.
Simplification of morphine gave pethidine and methadone.
Aims: improve potency, selectivity and pharmacokinetics (ADME) and reduce toxicity. Drug-likeness filters such as Lipinski's rule of five guide this.
Structure-based design (docking) needs the 3D target structure from X-ray crystallography, NMR or cryo-EM. Ligand-based design (pharmacophore models, QSAR) works when the target structure is unknown.
Chiral switches re-market a single enantiomer of an older racemate: esomeprazole, escitalopram, levocetirizine, levofloxacin.

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Lead sources

Source	Examples
Plants	Morphine, quinine, paclitaxel, artemisinin, digoxin
Microbes	Penicillin, streptomycin, statins (lovastatin)
Animal venoms	Captopril (snake venom), exenatide (lizard saliva)
Side effects	Sildenafil, minoxidil, sulfonylureas
Rational design	Cimetidine, captopril, imatinib, saquinavir

Irreversible (covalent) drugs

Drug	Target
Aspirin	COX (acetylation)
Penicillins	Penicillin-binding proteins
Omeprazole	H⁺/K⁺-ATPase
Phenoxybenzamine	α-Adrenoceptors
Organophosphates	Acetylcholinesterase
Clopidogrel	P2Y12 receptor

Memory aids

Covalent = Can't let go: Covalent binding is the strongest bond and usually makes a drug's effect irreversible.

Exam traps

Van der Waals forces are the weakest individually but add up over a large contact surface.
A chiral switch changes only the enantiomer, not the chemical structure.
Structure-based design needs the target's 3D structure; ligand-based design does not.
Captopril is the textbook example of rational drug design from a natural peptide lead.

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