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Binding Free Energy of Posaconazole in Two Protonation States to a Model of Captisol

posted May 17, 2019, 6:15 PM by Sheenam   [ updated May 19, 2019, 10:50 AM ]

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. However, its property as a weakly basic and poorly aqueous soluble drug results in poor bioavailability and variable absorption. Hence, for a better intravenous administration of the drug under aqueous conditions, the drug comes in a composition which consists of a solubilizing agent, a modified β-cyclodextrin such as Captisol which supposedly solubilizes with the drug in acidic medium. To test this hypothesis, we calculate the free binding energy of the drug Posaconazole to Captisol in different protonated states to understand the pH dependence of the observed solubility of posaconazole in the presence of Captisol via computational methods. The results of the computational experiments conducted here confirm the hypothesis that this effect is due to the higher affinity of the protonated form of Posaconazole relative to the unprotonated one.


Fig 1: Captisol-Posaconazole Complex (Posaconazole in Green)



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Sheenam,
May 17, 2019, 6:39 PM
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