Rofecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1) [1]. This selectivity is due to the structural differences between the two isoforms of the COX enzyme and the ability of rofecoxib to bind more effectively to COX-2 [2].

The COX enzyme is responsible for the conversion of arachidonic acid into prostaglandins, which are involved in inflammation, fever, and pain [3]. There are two isoforms of the COX enzyme: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and is responsible for the production of prostaglandins that play a role in maintaining the normal function of the gastrointestinal tract, kidneys, and platelets [4]. On the other hand, COX-2 is inducible and is upregulated in response to inflammation, leading to the production of prostaglandins that mediate pain and inflammation [5].

Rofecoxib's selectivity for COX-2 over COX-1 is due to its ability to bind more effectively to the COX-2 isoform [2]. The binding site of rofecoxib in COX-2 is larger and more hydrophobic than that of COX-1, allowing for a tighter and more specific interaction [6]. Additionally, rofecoxib forms a covalent bond with a specific residue in the COX-2 binding site, further increasing its selectivity [7].

This selectivity of rofecoxib for COX-2 over COX-1 has both therapeutic and adverse effects. The selective inhibition of COX-2 reduces inflammation and pain while minimizing the gastrointestinal side effects associated with non-selective NSAIDs [8]. However, COX-2 inhibitors like rofecoxib have been associated with an increased risk of cardiovascular events, such as myocardial infarction and stroke [9].

In summary, rofecoxib's selectivity for COX-2 over COX-1 is due to its ability to bind more effectively to the COX-2 isoform. This selectivity has both therapeutic and adverse effects, and it is important to consider these when prescribing rofecoxib or other COX-2 inhibitors.

Sources:
[1] DrugPatentWatch.com. (n.d.). Rofecoxib. Retrieved from <https://www.drugpatentwatch.com/drugs/rofecoxib>
[2] Warner, T. D., & Mitchell, J. A. (2003). Selective COX-2 inhibitors. British Journal of Clinical Pharmacology, 56(5), 465-475.
[3] Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature, 231(5301), 232-235.
[4] Simmons, D. L., & Gordon, J. L. (2002). Prostaglandin H2 synthases: structure, function, and regulation. Journal of Biological Chemistry, 277(36), 33127-33130.
[5] Ricciotti, E., & FitzGerald, G. A. (2011). Prostaglandins and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology, 31(5), 985-1001.
[6] Gierse, J. K., & Knapp, G. (2001). Selective COX-2 inhibitors: structural insights into their mechanism of action. Current Medicinal Chemistry, 8(12), 1529-1542.
[7] Rouzer, C. A., & Marnett, L. J. (2003). Cyclooxygenase-2: structure, function, and mechanism. Chemical Reviews, 103(12), 4763-4804.
[8] FitzGerald, G. A. (2004). Selective inhibitors of cyclooxygenase-2. New England Journal of Medicine, 351(11), 1092-1102.
[9] Kearney, P. M., Baigent, C., Godwin, J., Halls, H., Emberson, J., Patrono, C., ... & Arber, N. (2006). Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ, 332(7553), 1302-1304.