The role of human CYP2C8 in the metabolizing of montelukast-like compounds: a computational study

publication · 1 year ago
by Rahim Ghadari (University of Tabriz)
Calculator Plugins (logP logD pKa etc...) Marvin

Abstract Docking studies on the selected montelukast-like molecules with the CYP2C8 enzyme were done to investigate their interactions. The results showed that some of the investigated structures have competition with montelukast to bind to the CYP2C8, based on the similarity of their binding energies. Based on the docking results, different interactions between the investigated structures and CYP2C8 were observable such as hydrogen bonding, r–p, and cation–p interac- tions. A cation–p interaction between the Arg241 and chloroquinolin moiety was observable in most of the studied cases. A hydrogen bonding interaction between Ser100, Ser103, and Asn217 amino acids with the carboxylate moiety of the montelukast-like molecules was observable, as well. The CYP3A4, CYP2C8, and CYP2C9 have the role to oxidize montelukast to convert it to the more soluble compounds. This process was done by adding OH functional groups to it. New OH groups can facilitate its excretion from the body via kidneys by making it more hydrophilic. Therefore, the LogD values were considered as a measure of the ease of excretion. Based on the calculated LogD values, six of the studied structures will not obtain enough water solubility to be excreted from body by one oxidation process by the CYP2C8 enzyme and more of the oxidation process is needed. Between the studied structures, three of them showed the carboxylate moiety as the preferred binding site to the heme moiety. In total nine compounds need more of the oxidation process to obtain enough solubility to be excreted from the body.

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