Probing possible egress channels for multiple ligands in human CYP3A4: A molecular modeling study

Navaneethakrishnan Krishnamoorthy, Poornima Gajendrarao, Sundarapandian Thangapandian, Yuno Lee, Keun Woo Lee

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Human cytochrome P450 (CYP) 3A4 extensively contributes to metabolize 50% of the marketed drugs. Recently, a CYP3A4 structure with two molecules of ketoconazole (2KT) was identified. However, channels for egresses of these inhibitors are unexplored. Thus, we applied molecular dynamics simulations followed by channel analyses. Two simulations of empty and 2KT-bound CYP3A4 results revealed the multiple ligand-induced conformational changes in channel forming regions, which appear to be important for the regulation of channels. In addition, we observed that the channel-3 entrance is closed due to the large structural deviation of the key residues fromPhe-cluster. F215 and F220 are known as entrance blockers of channel-2 in metyrapone-bound CYP3A4. Currently, F220 blocks the channel-3 along with F213 and F241. Therefore, it suggested that channel-1 and 2 could potentially serve as egress routes for 2KT. It is also supported by the results from MOLAxis analyses, in which the frequency of channel occurrence and bottleneck radius during simulation favor channel-1 and 2. Several bottleneck residues of these channels may have critical roles in 2KT egresses, especially S119. Our modeling study for multiple ligand-channeling of CYP3A4 could be very helpful to gain new insights into channel selectivity of CYP3A4.

Original languageEnglish
Pages (from-to)607-614
Number of pages8
JournalJournal of Molecular Modeling
Volume16
Issue number4
DOIs
Publication statusPublished - 1 Jan 2010
Externally publishedYes

Fingerprint

egress
Cytochrome P-450 CYP3A
Molecular modeling
Ligands
ligands
Metyrapone
Ketoconazole
entrances
Molecular dynamics
simulation
cytochromes
Molecules
Computer simulation
inhibitors
Pharmaceutical Preparations
drugs

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Catalysis
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Probing possible egress channels for multiple ligands in human CYP3A4 : A molecular modeling study. / Krishnamoorthy, Navaneethakrishnan; Gajendrarao, Poornima; Thangapandian, Sundarapandian; Lee, Yuno; Lee, Keun Woo.

In: Journal of Molecular Modeling, Vol. 16, No. 4, 01.01.2010, p. 607-614.

Research output: Contribution to journalArticle

Krishnamoorthy, Navaneethakrishnan ; Gajendrarao, Poornima ; Thangapandian, Sundarapandian ; Lee, Yuno ; Lee, Keun Woo. / Probing possible egress channels for multiple ligands in human CYP3A4 : A molecular modeling study. In: Journal of Molecular Modeling. 2010 ; Vol. 16, No. 4. pp. 607-614.
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