This shows you the differences between two versions of the page.
Both sides previous revisionPrevious revisionNext revision | Previous revisionNext revisionBoth sides next revision | ||
home:publications:marshall_theoretical_2006 [04.24.2009] – neldawhite | home:publications:marshall_theoretical_2006 [03.08.2019] – [Editor's note] sallieq | ||
---|---|---|---|
Line 1: | Line 1: | ||
+ | |||
+ | ~~NOTOC~~ | ||
+ | |||
+ | |||
+ | ====== Paper - Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b ====== | ||
+ | |||
+ | |||
+ | **Type:** Paper\\ | ||
+ | **Author: | ||
+ | **Publication: | ||
+ | **Citation: | ||
+ | \\ | ||
+ | **See also:** [[http:// | ||
+ | |||
+ | |||
+ | |||
+ | ===== Abstract ===== | ||
+ | |||
+ | ==== Background ==== | ||
+ | |||
+ | There have been indications that common Angiotensin Receptor Blockers (ARBs) may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1, | ||
+ | |||
+ | ==== Results ==== | ||
+ | |||
+ | |||
+ | Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol) the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol) are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol) and Losartan (Ki≈70 nmol) may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol), while Losartan (Ki≈3 nmol), Irbesartan (Ki≈6 nmol), Olmesartan and Valsartan (Ki≈12 nmol) also seem likely to have significant PPAR modulatory activity. Olmesartan and Irbesartan (Ki≈9 nmol) additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1) has been presented. | ||
+ | |||
+ | ==== Conclusion ==== | ||
+ | |||
+ | Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ | ||
+ | {{tag> | ||
+ | |||
+ | ==== Editor' | ||
+ | |||
+ | (//since 2008// | ||
+ | < | ||
+ | |||
+ | 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, | ||
+ | |||
+ | 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, | ||