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2018 ; 58
(1
): 182-193
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Divergent Spatiotemporal Interaction of Angiotensin Receptor Blocking Drugs with
Angiotensin Type 1 Receptor
#MMPMID29195045
Singh KD
; Unal H
; Desnoyer R
; Karnik SS
J Chem Inf Model
2018[Jan]; 58
(1
): 182-193
PMID29195045
show ga
Crystal structures of the human angiotensin II type 1 receptor (AT(1)R) complex
with the antihypertensive agent ZD7155 (PDB id: 4YAY ) and the blood pressure
medication Benicar (PDB id: 4ZUD ) showed that binding poses of both antagonists
are similar. This finding implies that clinically used angiotensin receptor
blocking (ARB) drugs may interact in a similar fashion. However, clinically
observed differences in pharmacological and therapeutic efficacies of ARBs lead
to the question of whether the dynamic interactions of AT(1)R with ARBs vary. To
address this, we performed induced-fit docking (IFD) of eight clinically used
ARBs to AT(1)R followed by 200 ns molecular dynamic (MD) simulation. The
experimental K(i) values for ARBs correlated remarkably well with calculated free
energy with R(2) = 0.95 and 0.70 for AT(1)R-ARB models generated respectively by
IFD and MD simulation. The eight ARB-AT(1)R complexes share a common set of
binding residues. In addition, MD simulation results validated by mutagenesis
data discovered distinctive spatiotemporal interactions that display unique
bonding between an individual ARB and AT(1)R. These findings provide a reasonably
broader picture reconciling the structure-based observations with clinical
studies reporting efficacy variations for ARBs. The unique differences unraveled
for ARBs in this study will be useful for structure-based design of the next
generation of more potent and selective ARBs.
|*Drug Design
[MESH]
|Angiotensin II Type 1 Receptor Blockers/*chemistry/pharmacology
[MESH]
|Crystallography, X-Ray
[MESH]
|Humans
[MESH]
|Molecular Docking Simulation
[MESH]
|Molecular Dynamics Simulation
[MESH]
|Mutagenesis, Site-Directed
[MESH]
|Receptor, Angiotensin, Type 1/*chemistry/drug effects/genetics
[MESH]
free
free
free
