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

Content Provider	Springer Nature Link
Author	Krishnamoorthy, Navaneethakrishnan Gajendrarao, Poornima Thangapandian, Sundarapandian Lee, Yu Lee, Keun Woo
Copyright Year	2009
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 from Phe-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.
Starting Page	607
Ending Page	614
Page Count	8
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	16
Issue Number	4
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2009-08-29
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Channel Cytochrome P450 3A4 Ketoconazole Molecular dynamics simulation Multiple ligands Computer Application in Life Sciences Life Sciences Health Informatics Molecular Medicine Biomedicine general Computer Applications in Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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