Structure-based pharmacophore design and virtual screening for novel angiotensin converting enzyme 2 inhibitors.
The metallopeptidase Angiotensin Converting Enzyme (ACE) is an important drug target for the treatment of hypertension, heart, kidney, and lung disease. Recently, a close and unique human ACE homologue termed ACE2 has been identified and found to be an interesting new cardiorenal disease target. With the recently resolved inhibitor-bound ACE2 crystal structure available, we have attempted a structure-based approach to identify novel potent and selective inhibitors. Computational approaches focus on pharmacophore-based virtual screening of large compound databases. Selectivity was ensured by initial screening for ACE inhibitors within an internal database and the Derwent World Drug Index, which could be reduced to zero false positives and 0.1% hit rate, respectively. An average hit reduction of 0.44% was achieved with a five feature hypothesis, searching approximately 3.8 million compounds from various commercial databases. Seventeen compounds were selected based on high fit values as well as diverse structure and subjected to experimental validation in a bioassay. We show that all compounds displayed an inhibitory effect on ACE2 activity, the six most promising candidates exhibiting IC50 values in the range of 62-179 microM.
Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
Monika
M
Rella
Christopher A
CA
Rushworth
Jodie L
JL
Guy
Anthony J
AJ
Turner
Thierry
T
Langer
Richard M
RM
Jackson
D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D017706:Lisinopril / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry / Q000187:drug effects; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D008024:Ligands; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2