Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.
Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide-π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. a.m.hartman@student.rug.nl.
Alwin M
AM
Hartman
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. m.mondal@rug.nl.
Milon
M
Mondal
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany. radeva.neli@uni-marburg.de.
Nedyalka
N
Radeva
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany. Klebe@staff.uni-marburg.de.
Gerhard
G
Klebe
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. a.k.h.hirsch@rug.nl.
Anna K H
AK
Hirsch
D000215:Acylation; D001203:Ascomycota / Q000187:drug effects / Q000201:enzymology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D006835:Hydrazones; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase
aspartic protease endothiapepsin; inhibitors; molecular recognition; structure-based drug design