A three-dimensional construction of the active site (region 507-749) of human neutral endopeptidase (EC.3.4.24.11)

A three-dimensional model of the 507-749 region of neutral endopeptidase-24 .11 (NEP; E.C.3.4.24.11) was constructed integrating the results of seconda ry structure predictions and sequence homologies with the bacterial endopep tidase thermolysin. Additional data were extracted from the structure of tw o other metalloproteases, astacin and stromelysin. The resulting model acco unts for the main biological properties of NEP and has been used to describ e the environment close to the zinc atom defining the catalytic site. The a nalysis of several thiol inhibitors, complexed in the model active site, re vealed the presence of a large hydrophobic pocket at the S-1' subsite level . This is supported by the nature of the constitutive amino acids. The comp uted energies of bound inhibitors correspond with the relative affinities o f the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illu strated in the paper.