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home:publications:marshall_theoretical_2006 [03.07.2014] – [Results] sallieqhome:publications:marshall_theoretical_2006 [03.08.2019] – [Conclusion] sallieq
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 Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs. Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the activation of two key nuclear receptors-VDR and PPARgamma. If our simulations are confirmed by experiment, it is possible that ARBs may become useful as potent anti-inflammatory agents, in addition to their current indication as cardiovascular drugs.
 {{tag>papers Trevor_Marshall_PhD Frances_Marshall 2006 olmesartan vitamin_D}} {{tag>papers Trevor_Marshall_PhD Frances_Marshall 2006 olmesartan vitamin_D}}
 +
 +==== Editor's note ====
 +
 +Professor Marshall now says
 +<blockquote>I am certain that the primary mode of action of Olmesartan is agonism of the human VDR, and the subsequent reconditioning of the human immune system.
 +
 +I was conservative in that paper, and didn't claim Benicar as an agonist, but that had changed by Karolinska (as I collected more data) and now the molecular dynamics has firmly confirmed its remarkable similarity to 1,25-D in the VDR binding pocket (same residues, same hydrogen bonding, etc). Out of the pocket it is different in conformation, but my knowledge of the VDR has progressed to the point where I understand that only the top of the binding pocket is important, not the 'tail'.
 +
 +I am sure that olmesartan is active in some of the microbes. The early 1990's research on ARBs identified that fact. I am not sure what exactly the effect on the microbes is, if any. I don't think it is direct killing, as the difference we see between folks' reaction to Benicar are now being readily quantified in terms of their D metabolism (by both myself and Dr Greg Blaney).
 +
 +Our early papers say Benicar is an antagonist because 99% of molecules antagonize, and less than 1% activate receptors. So you always start from that perspective (an antagonist unless proven otherwise). After about 6 months of exploring all the possibilities, you will note that my description changed around the middle of last year. Now that we have produced the Molecular Dynamics videos/data, definitely showing the actions of an agonist, probably a super-agonist, I now know exactly how Olmesartan, 125-D, and 25-D, function in the VDR.</blockquote>
  
home/publications/marshall_theoretical_2006.txt · Last modified: 07.04.2022 by 127.0.0.1
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