From Catalytic Mechanisms to the Development of EMBM, a Computational Tool for the Designof TS Analog Inhibitors of Proteases

Mechanistic studies of catalysis and inhibition of serine and cysteine proteases afforded new and sometimes surprising insights, challenging conventional dogmas in enzymology. They provided a mechanistic basis for the understanding of the trend in binding affinity of “warheads” of reversible covalent transition-state analog (TS) inhibitors. These studies led us to the development of EMBM (enzyme mechanism based method), a unique CADD methodology for the prediction of binding affinity and the design of TS inhibitors. EMBM is unique among other computational tools by accounting for both covalent and non-covalent interactions of TS inhibitors with their target enzymes. The method was implemented in both ligand-based and structure-based design protocols, demonstrating its prediction ability on series of TS inhibitors of seven serine- and cysteine hydrolases. Thus, EMBM may provide a practical and efficient tool for the design of drugs that are based on TS analog inhibitors.