Sandbox CYPMetabolism: Difference between revisions
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It has been demonstrated that two or more smaller molecules may bind within an active site at the same time. In this case, drug metabolism can, strangely enough, actually be increased. It has been proposed that when only one molecule of a smaller drug (let's call this Drug A) is bound to the active site, that the extent of Drug A 's metabolism can be minimal due to the relatively large cavity. One explanation may be that Drug A isn't held in a sufficient orientation to the heme Iron. For optimum metabolism, the heme should bond with an Oxygen of the ligand. However, when two molecules of a smaller drug bind at the same time, one molecule may help in forcing the other molecule to retain proper orientation; thus, improving catalytic efficiency. This theory of two drugs binding simultaneously to a CYP may influence its pharmacokinetics is illustrated by the following structure of ketoconazole bound to a CYP enzyme ([[2v0m]]) <ref>PMID:16954191</ref>. | It has been demonstrated that two or more smaller molecules may bind within an active site at the same time. In this case, drug metabolism can, strangely enough, actually be increased. It has been proposed that when only one molecule of a smaller drug (let's call this Drug A) is bound to the active site, that the extent of Drug A 's metabolism can be minimal due to the relatively large cavity. One explanation may be that Drug A isn't held in a sufficient orientation to the heme Iron. For optimum metabolism, the heme should bond with an Oxygen of the ligand. However, when two molecules of a smaller drug bind at the same time, one molecule may help in forcing the other molecule to retain proper orientation; thus, improving catalytic efficiency. This theory of two drugs binding simultaneously to a CYP may influence its pharmacokinetics is illustrated by the following structure of ketoconazole bound to a CYP enzyme ([[2v0m]]) <ref>PMID:16954191</ref>. | ||
Ketoconazole is an anti-fungal drug that can have unusual pharmacokinetics; its apparent plasma concentration does not reflect what we would traditionally expect when considering the dose given. In the structure shown next, <scene name='60/609993/Cyp3a4/6'> two molecules of ketoconazole</scene> are bound to the CYP. You | Ketoconazole is an anti-fungal drug that can have unusual pharmacokinetics; its apparent plasma concentration does not reflect what we would traditionally expect when considering the dose given. In the structure shown next, <scene name='60/609993/Cyp3a4/6'> two molecules of ketoconazole</scene> are bound to the CYP. You will also notice that both molecules play a role in the drug being metabolized when the <scene name='60/609993/Cyp3a4/11'>binding pocket</scene> is displayed. One of the ketoconazole molecules is bound directly to the heme ring, while the second molecule has taken up residence in the pocket and appears to be ensuring the first one remain in place. You can see the relationship of the two ketoconazole molecules better if we <scene name='60/609993/Cyp3a4/10'>remove the protein</scene>. The unusual pharmacokinetics of ketoconazole may be explained by the fact that as its plasma concentration increases, the activity of the enzyme is altered due to two drugs now being bound. | ||
== Irreversible inhibition of CYP450s== | == Irreversible inhibition of CYP450s== | ||