The chemotherapeutic agent vincristine, used for treatment of acute lymphoblastic leukemia is
metabolized preferentially by polymorphic cytochrome P450 3A5 (CYP3A5) with higher clearance rate than
cytochrome P450 3A4 (CYP3A4). As a result, CYP3A5 expressers have a reduced amount of vincristine-induced
peripheral neuropathy than non–expressers. We modeled the structure of CYP3A5 and its interaction with
vincristine, compared with CYP3A4-vincristine complex using molecular docking and simulation studies. This
relative study helped us to understand the molecular mechanisms behind the interaction at the atomic level through
interaction energy, binding free energy, hydrogen bond and solvent accessible surface area analysis - giving an
insight into the binding mode and the main residues involved in this particular interaction. Our results show that the interacting groups
get closer in CYP3A5-vincristine complex due to different orientation of vincristine. This leads to higher binding affinity of vincristine
towards CYP3A5 compared to CYP3A4 and explains the preferential metabolism of vincristine by CYP3A5. We believe that, the results
of the current study will be helpful for future studies on structure-based drug design in this area.
Keywords: cancer, Cytochrome P450 3A5, Cytochrome P450 3A4, neurotoxicity, vincristine, vincristine-cytochrome interaction.
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