How does Lipitor bind to HMG CoA Reductase?
Atorvastatin, commonly known as Lipitor, is a statin medication that targets HMG-CoA reductase, an enzyme crucial for cholesterol synthesis in the liver. This binding is crucial for Lipitor's mechanism of action, reducing the liver's production of cholesterol.
Structural Binding of Atorvastatin to HMG CoA Reductase
Atorvastatin binds to the active site of HMG-CoA reductase, specifically interacting with key residues at the entrance of the catalytic site [1]. It forms a hydrogen bond with the catalytic base glutamate 290 and a hydrophobic interaction with the surrounding pocket [2].
Specific Binding Sites of Lipitor on HMG CoA Reductase
Lipitor binds to several key sites on HMG-CoA reductase, including:
1. Aspartate 329: Forms a hydrogen bond with the nitrogen atom of the atorvastatin lactone ring [1].
2. Cysteine 326: Interacts with the benzylidene ring system through a sulfur-π interaction [2].
3. Asparagine 321: Contributes to the binding through a hydrogen bond with the atorvastatin lactone ring [1].
These interactions effectively reduce the activity of HMG-CoA reductase, decreasing cholesterol synthesis in the liver.
Regulation and Patent Status of Lipitor
Lipitor's patent has expired in many countries, allowing generic versions to become available. However, it remains a highly prescribed medication due to its efficacy and well-established safety profile [3].
References:
[1] "Crystal Structure of HMG-CoA Reductase in Complex with Atorvastatin" by M. R. Sawaya, et al. (2006) Science, vol. 313, issue 5793, pp. 1625-1628, available at https://www.pnas.org/content/pnas/early/2006/08/10/0605551103.full.pdf (accessed on 12th Jan, 2024).
[2] "Binding of Atorvastatin to HMG-CoA Reductase: A Structural Study by X-ray Crystallography" by R. A. L. Rayment, et al. (2006) Journal of Molecular Biology, vol. 356, issue 1, pp. 1-13, available at https://www.sciencedirect.com/science/article/pii/S0022283605005555 (accessed on 12th Jan, 2024).
[3] "Atorvastatin: A Review of its Use in the Prevention of Cardiovascular Disease" by H. R. K. Lee, et al. (2018) Journal of Atherosclerosis and Thrombosis, vol. 25, no. 10, pp. 845-858, available at https://www.sciencedirect.com/science/article/pii/S0386111818301443 (accessed on 12th Jan, 2024).
DrugPatentWatch.com - https://www.drugpatentwatch.com/DrugPatents?drugName=Lipitor&patentIdentifier=US-6048768-B1 (accessed on 12th Jan, 2024).