Enzymology

Mark Namchuk - Vertex

Vertex x Chinese labs mega study:

- Target validation (human genetics + molbio) BUT, if you don’t link it to the therapeutic intervention, 2/3s don’t work!

- Need to separate and actually

- Basics of enzymology and impact on screening and med chem data

- Basically all enzyme drugs are inhibitors. They inhibit the enzymes

- Michaelis-Menten Equation

- Enzymes get saturated by your substrate which asymptotes at Vmax

- Binding reaction is Km and ES -> E + P is Kcat

- Km is the amount of substrate where V = 1/2 of Vmax

- Multisubstrate reactions become exponentially more difficult to model

- Alpha factor = ternary (protein bound to 2 substrates); bind to substrate A -> leads to increase in substrate B

- You want an inhibitor not a binder. Look at effects on enzyme inhibition, not just binding affinity

- Competitive, non-competitive, uncompetitive inhibition

- Condition selection for screening/counter-screening

- When do on and off rates matter and why?

- Equilibrium and non-equilibrium systems

- When to measure on and off rates and why

- Case study for COX-2 inhibitors

- Case study for Telaprevir