Structure-based inhibitor design by using protein models for the development of antiparasitic agents.
The lack of an experimentally determined structure of a target protein frequently limits the application of structure-based drug design methods. In an effort to overcome this limitation, we have investigated the use of computer model-built structures for the identification of previously unknown inhibitors of enzymes from two major protease families, serine and cysteine proteases. We have successfully used our model-built structures to identify computationally and to confirm experimentally the activity of nonpeptidic inhibitors directed against important enzymes in the schistosome [2-(4-methoxybenzoyl)-1-naphthoic acid, Ki = 3 microM] and malaria (oxalic bis[(2-hydroxy-1-naphthylmethylene)hydrazide], IC50 = 6 microM) parasite life cycles.
Ring
C S
CS
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
Sun
E
E
McKerrow
J H
JH
Lee
G K
GK
Rosenthal
P J
PJ
Kuntz
I D
ID
Cohen
F E
FE
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010196:Pancreatic Elastase / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D012547:Schistosoma / Q000187:drug effects / Q000502:physiology; D012556:Schistosomicides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D000962:Antimalarials; D011480:Protease Inhibitors; D012556:Schistosomicides; D010450:Endopeptidases; D010196:Pancreatic Elastase