Vinca alkaloids are chemotherapeutic agents used in the treatment of both pediatric and adult cancer patients. Cytochrome P450 3A5 (CYP3A5) is 9- to 14-fold more efficient at clearing vincristine than cytochrome P450 3A4 (CYP3A4) is. However, patients who express an inactive form of the polymorphic CYP3A5 enzyme suffer from severe neurotoxicity during vincristine treatment, resulting in chemotherapy failure. Previous studies have found that the addition of new features to the parent drug can enhance its binding affinity to tubulin manyfold and could therefore yield novel anticancer drugs. However, there is no report of any study of the metabolic activities of CYP3A4 and CYP3A5 with respect to vincristine and vinblastine, so we studied the interactions of these two drugs and 15 vinca derivatives with CYP3A4 and CYP3A5 by performing docking studies using GOLD. Six of the vinca derivatives in complexes with CYP3A4 and CYP3A5 were further investigated in 100-ns molecular dynamic simulations. Interaction energies, hydrogen bonds, and linear interaction energies were calculated and principal component analysis was carried out to visualize the binding interface in each complex. The results indicate that the addition of dimethylurea at the C20' position in vincristine may increase its binding affinity and lead to enhanced interactions with the less polymorphic CYP3A4 rather than CYP3A5. Thus, dimethylurea vincristine may be a useful drug in cancer chemotherapy treatment as it should be significantly less likely than vincristine to induce severe neurotoxicity in patients. Graphical Abstract Proposed modification of Vinca alkaloid derivatives to decrease the neurotoxicity level in cancer patients exhibiting CYP3A4 gene rather than polymorphic CYP3A5 gene.
Keywords: Chemotherapeutic agents; Cytochrome P450 3A4; Cytochrome P450 3A5; Dimethylurea vincristine; Neurotoxicity; Vincristine and vinblastine derivatives.