Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs

- 'Chameleonic' behavior is known to be important for the bioavailability of certain macrocyclic drugs.
- We show that some degree of chameleonic behavior is required for most oral drugs with MW > 600-700 Da.
- A compound likely requires chameleonic properties if either TPSA < 0.2 × MW, or MPSA in nonpolar environments >140 Å2.
- Chameleonic behavior potentially explains the improved properties of the high MW Bcl-xL inhibitor ABT263 compared to ABT737.
- A change in exposed PSA of ≥0.2 MW - 140 Å2 is required for effective chameleonic behavior.