PN: Drug Discovery

• safe and non-toxic

• as few side effects as possible

• chemically and metabolically stable

• easy to obtain/synthesize

• soluble in water in the therapeutic concentration (no precipitation in the blood stream!)

• soluble in lipids (to be able to cross lipid membranes)

• accessibility, safety, therapeutic effect

Lipinski’s rule of five

• < 500 Da

• < 5 H-bond donors

• < 10 H-bond acceptors

• octanol-water partition coefficient: log(P) < 5

• < 10 rotatable bonds

• the effect of the drug on the body: pharmacodynamics

  • mechanism of drug action

  • effect of the concentration of the drug

  • adverse reactions

• the effect of the body on the drug: pharmacokinetics (ADME processes)

  • absorption

  • distribution

  • metabolism

  • excretion

• identification of active substances of traditional drugs (herbs etc.) / discovery by chance

  • e.g.: penicillin

• chemical modification of known drugs/natural products

  • e.g.: aspirin

• database screening

  • e.g.: prontosil

• rational drug design

• ligand-based

  • structure of target macromolecule is unknown

  • structure of the ligand is designed and optimized

• structure-based

  • structure of target macromolecule is known

  • ligand is designed complementary to the active site of the target molecule

• Lead discovery

  • lead compound: prototype drug that needs further improvement

  • approaches for discovery:

    • serendipity

    • endogenous source (use or mimic compound that occurs in humans)

    • exogenous source (use or mimic compound that occurs in other life forms)

    • rational drug design (database searches for non-naturally occurring compounds, e.g. GBD-17)

• Optimization of ADME parameters (most difficult step)

• asses ADME parameters and activity (descriptors, assays)

• High-Throughput Screening (screening of drug target against a selection of chemicals)

• library development (helps in HTS and target identification)

• structure-activity relationship (SAR)

  • helps identifying the pharmacophore (the part of the molecule that is responsible for its activity

  • helps find more active compounds

• in-silico screening

  • helps finding ligands that are likely to bind to the target

• chemical synthesis

  • synthesis of the lead compound (sufficiently pure and sufficient quantity)

• optimization for bulk production

• development of suitable formulation

• test in animals

• behavioral studies, functional imaging

• ex-vivo studies (on tissue samples)

phase I: healthy volunteers (20-50 people, 1 month)

• toxicity

• tolerated dosage

• pharmacology

phase II: healthy volunteers (50-300 people, 3-12 months)

• safety

• toxicity/drug interactions

• efficacy

phase III: patients (250-1000 people, 6-12 months)

• safety

• comparison with other drugs

• do the benefits outweigh the risks?

phase IV: post-marketing surveillance

• after FDA approved the drug

• detection of rare or long-term effects

• means to describe dose-effect relationship (how much of a drug is necessary to obtain the desired effect)

• mode of action: location and mechanism how the drug produces its effect

• can help

  • with safety considerations

  • find the correct dose

  • identify possible side-effects