Identification of a less toxic vinca alkaloid derivative for use as a chemotherapeutic agent, based on in silico structural insights and metabolic interactions with CYP3A4 and CYP3A5

  • Nikhat Saba
  • Alpana Seal
Original Paper


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.


Vincristine and vinblastine derivatives Dimethylurea vincristine Chemotherapeutic agents Neurotoxicity Cytochrome P450 3A4 Cytochrome P450 3A5 



Molecular dynamics simulation


Cytochrome p450 3A4/5


Root mean square deviation


Root mean square fluctuation


Van der Waals


Hydrogen bond



We acknowledge the University Grants Commission for MANF, the DST-Purse program, and the BTIS net program of DBT, the Government of India, New Delhi for financial support. We thank Dr. Suman Kumar Nandy and Shri Rajabrata Bhuyan for reading the manuscript and their helpful suggestions.

Supplementary material

894_2018_3611_MOESM1_ESM.docx (5.9 mb)
ESM 1 (DOCX 6083 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and BiophysicsUniversity of KalyaniKalyaniIndia

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