Computer-aided design of novel inhibitors of human leukocyte elastase

Abstract

Publisher Summary This chapter discusses computer-aided design of novel inhibitors of human leukocyte elastase (HLE). HLE is a member of the serine protease family of enzymes and is contained in the azurophilic granules of human neutrophils. It is released from neutrophils in response to inflammatory stimuli and has been implicated in the development of various diseases such as emphysema, cystic fibrosis, and chronic bronchitis. Under normal conditions the body protects itself from the potentially damaging effects of extracellular HLE with endogenous inhibitors such as alpha-1-proteinase inhibitor (α 1 -PI) and secretory leukocyte protease inhibitor (SLPI). A variety of HLE inhibitors have been reported, including the peptidyl trifluoromethyl (TFMKs), α-ketobenzoxazoles, β-lactams and others. TFMK inhibitors function by interacting with the active site serine 195 hydroxyl group to give a hemiketal which is an analogue of the tetrahedral intermediate formed in the normal HLE-catalyzed hydrolysis reaction of amide bonds. Examination of the pyridone derivative in the active site model indicates that the absence of the proline ring significantly reduces the hydrophobic interaction with the S2 pocket of HLE.