Theoretical analysis of peptidyl α-ketoheterocyclic inhibitors of human neutrophil elastase: Insight into the mechanism of inhibition and the application of QM/MM calculations in structure-based drug design

Abstract

It has been suggested from QSAR data (P. D. Edwards, D. J. Wolanin, D.A. Andisik and M. W. Davis, J. Med. Chem., 1995, 38, 76) that the inhibition of elastase by peptidyl α-ketoheterocyclic inhibitors can occur in two ways, the less potent inhibitors forming a non-bonded Michaelis complex and the more potent set a covalently bonded enzyme–substrate intermediate. We report QM/MM studies of both binding and reactivity that confirm these findings, showing that the activity of the least potent set of inhibitors correlates with the calculated binding energy, and that of the more potent set correlates with the stability of the intermediate. These calculations show that QM/MM methods can be successfully employed to understand complicated structure-activity relationships and might be employed in the design and assessment of new inhibitors.