Shows tendency for mergers. These big companies may be shrinking – much research is now outsourced to low cost countries like Latvia, India, China and to small Biotech companies. The Biotech. companies (<50 people?) use the profits of contract work to fund their own research projects Commercial aspects £500M, years to develop a drug, patent life 25 years from the start of the process Not examinable

Phase 1: Tolerance in healthy volunteers, Highest tolerable dose, Smallest effective dose Dose/effect relationship, Duration of effect Side effects, Pharmacokinetics in man Phase 2: First controlled trials on efficacy in the patient Bioavailability testing of formulations Phase 3: Large scale trials at several clinical centres, Establish therapeutic profile: Indications, Dosage and administration, Contraindications, Side effects Proof of efficacy and safety in the long-term. Demonstration of therapeutic advantage e.g. QSAR e.g. Screening (HTS & virtual screening Overview of Drug Design

Whole cell v. target-based screening strategies Whole-cell screening (looking directly for compounds which kill micororganisms) Advantages Selection for compounds that penetrate cells Antimicrobial properties established Highly reproducible Used successfully historically Disadvantages Insensitive Most active compounds are toxic No rational basis for compound optimization (target unknown) Mixed mechanism of action In recent years has failed to deliver Target-based screening (looking for biochemical inhibition) Advantages More sensitive – can detect weak or poorly penetrating compounds suitable for optimization Easy screening Different approach Can target new areas of biology (i.e. new mechanisms) Facilitates rational drug design Disadvantages Need to turn an in vitro inhibitor into an antibacterial drug (complicated by penetration issues) Genetic validation of targets by gene knockout or low expression can be misleading Effective drugs may hit more than 1 target Not examinable

1.3.1 High throughput screening uses modern technology Not examinable

No pipetting to add compounds! Not examinable

Needs sufficient well-chosen molecules i.e. it must easy to chemically modify the compounds e.g. nitro groups as such compounds can be metabolized to carcinogens So we have to think carefully to cut down the number – e.g. if many compounds similar, only screen 1 If we know something about the nature of active compounds, focus on such – focused screening. Use modelling / virtual (docking) screening / pharmacophore screening (cf 5HT 3 activity) / commercial databses of compounds known to bind to target or a related target etc. to select a small set to screen The screening collection Obey Lipinski’s rule of 5

An example of the use of knowledge databases for finding actives Not examinable