Losartan's molecular basis of interaction with membranes and AT1 receptor.
Physicochemical methods were used to study the thermal and dynamic changes caused by losartan in the membrane bilayers. In addition, molecular modeling was implemented to explore its topography both in membranes and AT(1) receptor. Its incorporation resulted in the modification of thermal profile of dipalmitoyl phosphatidylcholine (DPPC) bilayers in a concentration dependent way up to 20mol% as it is depicted from the combination of differential scanning calorimetry (DSC) and MAS data. In particular, the presence of losartan caused lowering of the phase transition temperature and abolishment of the pretransition. T(1) experiments revealed the location of the drug into the membrane bilayers. The use of a combination of biophysical methods along with docking experiments brought out a possible two-step mechanism which involves incorporation of losartan at the interface of membrane bilayers and diffusion in the upper parts of AT(1) receptor helices IV-VII.
Zoumpoulakis
P
P
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, 11635, Athens, Greece.
Daliani
I
I
Zervou
M
M
Kyrikou
I
I
Siapi
E
E
Lamprinidis
G
G
Mikros
E
E
Mavromoustakos
T
T
D002152:Calorimetry, Differential Scanning; D002462:Cell Membrane / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D019808:Losartan / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013696:Temperature
D008563:Membrane Lipids; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan