Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations

Haiting Lu, Xiaoqin Huang, Mohamed Diwan M. Abdulhameed, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, that is, the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally-derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors.

Original languageEnglish
Pages (from-to)2149-2156
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number7
StatePublished - Apr 1 2014

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health (Grant RC1 MH088480 to Zhan) and the National Science Foundation (Grant CHE-1111761 to Zhan). In addition, Lu thanks the Henan Education Department of China (for Science and Technology Key Project grant No. 2011B150031 ) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars of the Ministry of Education , China (for grant No. 2012940 ). The authors also acknowledge the Center for Computational Sciences (CCS) at the University of Kentucky for supercomputing time on IBM X-series Cluster with 340 modes or 1360 processors.


  • Binding free energy
  • Enzyme inhibitor
  • Molecular modeling
  • Nicotine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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