Molecular Modelling of the Active Site of Enkephalin‐Degrading Neutral Endopeptidase‐24.11 (Enkephalinase) An Active Site Model for Neutral Endopeptidase‐24.11

Abstract

AbstractThe active site regions of thermolysin (TLN) and carboxypeptidase A (CPA) are directly compared by superimposition of the published crystal structures of eight TLN/inhibitor complexes and four CPA‐inhibitor complexes. There is a remarkable similarity in the S′1 region of these two zinc metalloenzymes, and it is suggested that this may be a common feature among other enzymes of this class, including the enkephalin‐degrading neutral endopeptidase or “enkephalinase” (NEP‐24.11). Assuming this common feature, the possible geometry of the S′2 region of enkephalinase was determined by performing classical potential energy calculations on potent NEP‐24.11 inhibitors. The active conformation of these inhibitors was thus identified as similar to that found in the X‐ray crystal structure of TLN/inhibitor complexes. It is proposed that the active site region of TLN should serve as a reasonable model for that of NEP‐24.11. Extension of the model to the case of angiotensin‐converting enzyme (ACE) showed that this enzyme might have a similar S′1 region to the other three enzymes, and allowed further definition of the ACE model previously developed in our laboratory.