Optimizing leads
- Protein structure-based
drug design cycle.
- Lead compounds originate
from random
screening of a few
hundred thousand compounds.
- Lead compounds from
design - In this case, synthesis can be bypassed by
using docking of compounds available commercially or in-house.
Design is the result of docking,
linking and building, or any combination of the three. Due to the
imperfections of computer scoring, only about 2% of the
designed compounds pass the first criterion to become a lead,
namely having micromolar affinity.
- Verification of the
structure of the protein-lead complex is essential.
- New rounds of
structure-based
design are then
performed until a promising compound shows up for pre-clinical
trials. At this stage the structure is still useful: knowledge
of the essential protein-ligand
interactions
dictates where structural modifications to improve the
pharmacodynamic properties should not be made.
- After successful clinical
trials a new drug is born.
