A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4.
Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson-Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs.
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. suresh@ajou.ac.kr.
Suresh
S
Panneerselvam
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. dhanusha@ajou.ac.kr.
Dhanusha
D
Yesudhas
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. prasanna@ajou.ac.kr.
Prasannavenkatesh
P
Durai
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. ayaz@ajou.ac.kr.
Muhammad Ayaz
MA
Anwar
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. gosu@ajou.ac.kr.
Vijayakumar
V
Gosu
Department of Molecular Science and Technology, Ajou University, Suwon 443-749, Korea. sangdunchoi@ajou.ac.kr.
Sangdun
S
Choi
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D062105:Molecular Docking Simulation; D013816:Thermodynamics
D000970:Antineoplastic Agents; D051544:Cytochrome P-450 CYP3A
CYP450; docking; drug metabolism; molecular dynamics simulation