Free Energy Calculations Assess Covalent Inhibitor Binding to Cruzain and Cathepsin L
- Uses relative binding free energy (FEP-type alchemical) calculations to compare warhead-bearing covalent inhibitors across two related cysteine proteases.
- Cruzain, the key protease of Trypanosoma cruzi (Chagas disease), and human cathepsin L, its close homolog, are modeled in parallel.
- Comparison highlights selectivity for the parasitic target versus off-target reactivity with the human enzyme, guiding optimization.
💡 Points
FEP on a reactive warhead is still shakier than on reversible binders — parameterizing the covalent bond is where these methods quietly break. Still, cat L cross-reactivity has sunk more cruzain leads than weak potency ever did, so a validated ΔΔG ranking that flags off-target binders before synthesis is real triage value — worth having when neglected-disease budgets don't cover redundant chemistry.