Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Targeted covalent inhibition enhances drug potency and selectivity.
• Balancing warhead reactivity is crucial for efficacy and safety.
• Predicting reactivity is key to designing effective covalent inhibitors.

Purpose of the Study:

• To assess experimental and computational methods for predicting glutathione adduct half-life (GSH t_1/2).
• To evaluate a novel pK_a-based method for predicting warhead reactivity.
• To identify structure-activity relationships for cysteine-targeting covalent warheads.

Main Methods:

• Assessed glutathione (GSH) t_1/2 assay for cysteine-targeting covalent warheads.
• Employed experimental and computational approaches for reactivity prediction.
• Utilized matched molecular pairs analysis on an internal compound collection.

Main Results:

• Evaluated multiple methods for predicting GSH t_1/2.
• Introduced and assessed a novel pK_a-based prediction method.
• Revealed structure-activity relationships for various covalent warheads.

Conclusions:

• Accurate prediction of warhead reactivity is achievable through various methods.
• The novel pK_a-based approach shows promise for predicting GSH t_1/2.
• Findings will guide the rational design of covalent inhibitors with tailored reactivity.