Cytochrome P450 2C9 polymorphism: Effect of amino acid substitutions on protein flexibility in the presence of tamoxifen.

Cytochrome P450 2C9 polymorphism: Effect of amino acid substitutions on protein flexibility in the presence of tamoxifen. Comput Biol Chem. 2019 Nov 17;:107166 Authors: Manish M, Lynn AM, Mishra S Abstract Tamoxifen is a prodrug and cytochrome P450 2C9 (CYP2C9) has a significant role in the formation of a therapeutically more potent metabolite (4-hydroxytamoxifen) than tamoxifen. Since CYP2C9 exhibits genetic polymorphism, it may contribute to different phenotypic drug response. Moreover, it may be misleading if the possibility of heterogeneous clinical observations of pharmacogenetic investigations is ignored. Above all, clinical investigation of all the polymorphic variants is beyond the scope of a pharmacogenetic study. Therefore, in order to understand the genotype-phenotype association, it is aimed to study the interatomic interactions of amino acid substitutions in CYP2C9 variants in the presence of tamoxifen. Computational structural biology approach was adopted to study the effect of amino acid substitutions of polymorphic variants of CYP2C9 R144C (*2), I359 L (*3), D360E (*5), R150H (*8), R335W (*11) and L90 P (*13) on the flexibility of the enzyme in the presence of tamoxifen. The mutations were selected based on previously determined associations on genotype and clinical outcome of drugs. Against the above plane, docking of tamoxifen was performed with the crystal structure representing the wild-type form of the enzyme...
Source: Computational Biology and Chemistry - Category: Bioinformatics Authors: Tags: Comput Biol Chem Source Type: research