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Structure-based design of parasitic protease inhibitors.

Abstract：

:To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compuo enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthyl-methylene)hydrazide (1) [Ring, C. S.; Sun, E.; McKerow, J. H.; Lee, G.; Rosenthal, P. J., Kuntz, I. D.; Cohen, F. E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC50 6 microM) and the organism in vitro as judged by hypoxanthine uptake (IC50 7 microM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC50 150 nM) and chalcones (IC50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 A, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC50 600 microM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Li R,Chen X,Gong B,Selzer PM,Li Z,Davidson E,Kurzban G,Miller RE,Nuzum EO,McKerrow JH,Fletterick RJ,Gillmor SA,Craik CS,Kuntz ID,Cohen FE,Kenyon GL

doi

10.1016/0968-0896(96)00136-8

subject

Has Abstract

pub_date

1996-09-01 00:00:00

pages

1421-7

issue

eissn

0968-0896

issn

1464-3391

pii

0968-0896(96)00136-8

journal_volume

pub_type

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Structure-based design of parasitic protease inhibitors.