Sandbox 123456: Difference between revisions

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The primary component of Noxafil, posaconazole (green link) is a potent, broad-spectrum antifungal drug. It was derived from a similar triazole antifungal agent, Itraconazole. The differences in structure are that the chlorine substituents in the aromatic ring on the left-hand side of the images are replaces with fluorines (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref name="drugbank">Posaconazole. (n.d.). Retrieved from https://www.drugbank.ca/drugs/DB01263

Accession Number: DB01263 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.

Accession Number: DB01263 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of the CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.

(explanation of green links/figures?)

==Mechanism==

When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) ~~which~~ prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species <ref name="formularyjournal" />.

When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor through an ionic bond between a neutral nitrogen atom on posaconazole and an iron atom on heme (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51). This prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species <ref name="formularyjournal" />.

== Relevance ==

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 The primary component of Noxafil, posaconazole (green link)  is  a potent, broad-spectrum antifungal drug. It was derived from a similar triazole antifungal agent, Itraconazole. The differences in structure are that the chlorine substituents in the aromatic ring on the left-hand side of the images are replaces with fluorines (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref name="drugbank">Posaconazole. (n.d.). Retrieved from https://www.drugbank.ca/drugs/DB01263
-Accession Number: DB01263 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.
+Accession Number: DB01263 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of the CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.
 (explanation of green links/figures?)
 ==Mechanism==
-When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) which prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species <ref name="formularyjournal" />.
+When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor through an ionic bond between a neutral nitrogen atom on posaconazole and an iron atom on heme (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51). This prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species <ref name="formularyjournal" />.
 == Relevance ==