Diffusion Limit and the Reactivity/Affinity Conundrum: Implications for Optimization and Hit Finding for Irreversible...

Area of Science:

• Medicinal Chemistry
• Chemical Kinetics
• Drug Discovery

Background:

• Irreversible inhibition is a key therapeutic strategy, gaining prominence in the last decade.
• Current drug design often balances small molecule affinity with electrophile reactivity to minimize off-target effects.
• Limited theoretical frameworks exist for designing effective irreversible inhibitors.

Purpose of the Study:

• To challenge the conventional approach in irreversible inhibitor design.
• To propose a kinetic limit for the inactivation rate constant over the inhibition constant (k_inact/K_I).
• To explore the implications of this kinetic limit on drug discovery and optimization.

Main Methods:

• Kinetic analysis of irreversible inhibition.
• Theoretical evaluation of rate-limiting steps in molecular interactions.
• Discussion of implications for drug design strategies.

Main Results:

• The inactivation rate constant over the inhibition constant (k_inact/K_I) is physically limited by diffusion rates.
• Attempts to enhance small molecule affinity at this limit necessitate a trade-off in reactivity.
• This kinetic capping affects hit finding and lead optimization for irreversible inhibitors.

Conclusions:

• The design of irreversible inhibitors is constrained by fundamental kinetic principles.
• Optimization strategies must account for the diffusion-limited trade-off between affinity and reactivity.
• This understanding is crucial for developing drugs against challenging targets, particularly those with shallow binding pockets.