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conferenceseries
.com
Volume 8
Medicinal Chemistry
ISSN: 2161-0444
Medicinal Chemistry 2018
June 14-15, 2018
June 14-15, 2018 | Barcelona, Spain
10
th
World Congress on
Medicinal Chemistry and Drug Design
Role of dynamic nonprime binding of sampatrilat for the development of domain selective inhibitors
Rajni Kant Sharma
1, 2
, Horacio Poblete
3
, Ross G Douglas
2
, Edward D Sturrock
2
, Julio Caballero
3
and
Kelly Chibale
2
1
Kurukshetra University, India
2
University of Cape Town, South Africa
3
Universidad de Talca, Chile
S
ampatrilat is a vasopeptidase inhibitor that inhibits both angiotensin I-converting enzyme (ACE) and neutral endopeptidase.
ACE is a zinc dipeptidyl carboxypeptidase that contains two extracellular domains (nACE and cACE). In this study
the molecular basis for the selectivity of sampatrilat for nACE and cACE was investigated. Enzyme inhibition assays were
performed to evaluate the
in vitro
ACE domain selectivity of sampatrilat. The inhibition of the Cdomain (Ki=13.8 nM) by
sampatrilat was 12.4-fold more potent than that for the N-domain (171.9 nM), indicating differences in affinities for the
respective ACE domain binding sites. Interestingly, replacement of the P2 group of sampatrilat with an aspartate abrogated
its C-selectivity and lowered the potency of the inhibitor to activities in the micromolar range. The molecular basis for this
selective profile was evaluated using molecular modeling methods. We found that the C-domain selectivity of sampatrilat is
due to occupation of the lysine side chain in the S1 and S2 subsites and interactions with Glu748 and Glu1008, respectively.
This study provides new insights into ligand interactions with the nonprime binding site that can be exploited for the design
of domain selective ACE inhibitors.
rajniorganic@gmail.comMed chem (Los Angeles) 2018, Volume 8
DOI: 10.4172/2161-0444-C1-040