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home:publications:marshall_days_of_molecular_medicine_2007 [11.30.2008] – paulalbert | home:publications:marshall_days_of_molecular_medicine_2007 [09.14.2022] (current) – external edit 127.0.0.1 | ||
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+ | ~~NOTOC~~ | ||
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+ | ====== Poster - Molecular static and dynamic analyses reveal flaw in murine model used by US FDA to detect drug carcinogenicity ====== | ||
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+ | **Type:** Abstract presentation\\ | ||
+ | **Presented by:** Trevor Marshall, PhD\\ | ||
+ | **Conference: | ||
+ | **Location: | ||
+ | **Date: | ||
+ | **Additional content:** [[https:// | ||
+ | |||
+ | |||
+ | ===== Abstract ===== | ||
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+ | |||
+ | The US FDA currently accepts carcinogenicity studies of | ||
+ | pharmaceutical drugs based on murine models. In addition to 6 month | ||
+ | studies with p53(+/-) and ras.H2 transgenic mice, lifetime studies | ||
+ | (typically 2 years) in WT mice or rats are also considered as evidence | ||
+ | that a drug lacks carcinogenic activity. This model is not always | ||
+ | exhaustive. For example, during the acceptance testing of the ARB | ||
+ | Olmesartan((FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL | ||
+ | https:// | ||
+ | able to be duplicated in rats, or in transgenic mice. We have previously | ||
+ | used the static molecular modeling of AutoDock to demonstrate that | ||
+ | Olmesartan has agonostic activity in the PDB:1DB1 model of the | ||
+ | human VDR Nuclear Receptor((Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from | ||
+ | Chronic Inflammatory and Autoimmune Disease. | ||
+ | Abstract presentation, | ||
+ | the PDB:1RK3 model of the rat VDR. This agonism has now been | ||
+ | confirmed with Molecular Dynamics, using GROMACS. The murine | ||
+ | VDR indeed lost its ability to bind the DRIP 205 co activator when | ||
+ | Olmesartan was the ligand, while the human VDR was activated by | ||
+ | Olmesartan similarly to its native ligand (1, | ||
+ | Since the VDR is believed to express 913 genes(({{pmid> | ||
+ | This video was created using the GROMACS Molecular | ||
+ | Dynamics software on a small computing cluster assembled | ||
+ | from PCs based on Core-2-duo CPU technologies. The | ||
+ | difference in steady-state ligand conformation between | ||
+ | human and rat VDR can clearly be seen at | ||
+ | https:// | ||
+ | known to be associated with cancer pathogenesis, | ||
+ | between human VDR, and the animal model VDR, is exceedingly | ||
+ | important. | ||
+ | |||
+ | ==== Conclusion ==== | ||
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+ | The murine environment is inadequate to accurately | ||
+ | model drug carcinogenic activity in humans. A species should be | ||
+ | chosen which has a VDR LBP homology closer to that of man. AutoDock | ||
+ | and GROMACS molecular analyses are useful in resolving any | ||
+ | remaining anomalies in the observed data. | ||
+ | |||
+ | {{tag> | ||
+ | |||
+ | |||
+ | ===== References ===== | ||
+ | |||