Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2322–2335 | Cite as

Molecular docking simulations and GRID-independent molecular descriptor (GRIND) analysis to probe stereoselective interactions of CYP3A4 inhibitors

Original Research


CYP3A4 has been identified as a major enzyme involved in the metabolism of drugs and xenobiotics in the human body. It is mainly expressed in the liver and has a wide capacity to oxidize structurally and functionally diverse compounds due to its large promiscuous catalytic binding site. Inhibition of CYP3A4 often leads to undesired drug–drug interactions and toxic side effects. Previous studies have demonstrated that enantiomers of the same chiral drug might inhibit CYP3A4 with different potencies and thus, one enantiomer might have different pharmacokinetics, and metabolism as compared to its counterpart. Therefore, the use of enantiopure therapeutic agents has been advocated as a promising concept to evade drug toxicity. This emphasizes the need to investigate the molecular basis of interaction and stereoselectivity of CYP3A4. Towards this goal, various in silico models have been developed that correlate the differences in the inhibitory potencies of enantiomeric pairs with difference in their interaction pattern within the binding cavity of CYP3A4. The 3D interaction based differentiating features include two hydrogen bond acceptors at a certain distance from each other, as well as from molecular boundaries of different enantiomeric pairs. Additionally, our results demonstrated the role of a hydrogen bond donor and a hydrogen bond acceptor in stereoselective inhibition of CYP3A4.

Graphical Abstract

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For this type of study formal consent is not required


Cytochrome P450 (CYP-P450) Drug metabolism CYP3A4 inhibitors Stereoselectivity GRIND Molecular docking 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1933_MOESM1_ESM.docx (699 kb)
Supplementary Item I
44_2017_1933_MOESM2_ESM.xlsx (29 kb)
Supplementary Item II


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Sadia Mukhtar
    • 1
  • Yusra Sajid Kiani
    • 1
  • Ishrat Jabeen
    • 1
  1. 1.Research Center for Modeling and Simulation (RCMS)National University of Sciences and Technology (NUST)IslamabadPakistan

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