PT  - JOURNAL ARTICLE
AU  - Weihua Li
AU  - Hong Liu
AU  - Xiaomin Luo
AU  - Weiliang Zhu
AU  - Yun Tang
AU  - James R. Halpert
AU  - Hualiang Jiang
TI  - Possible Pathway(s) of Metyrapone Egress from the Active Site of Cytochrome P450 3A4: A Molecular Dynamics Simulation
AID  - 10.1124/dmd.106.014019
DP  - 2007 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 689--696
VI  - 35
IP  - 4
4099  - http://dmd.aspetjournals.org/content/35/4/689.short
4100  - http://dmd.aspetjournals.org/content/35/4/689.full
SO  - Drug Metab Dispos2007 Apr 01; 35
AB  - To identify a possible pathway(s) for metyrapone egress from the active site of P450 3A4, a 5-ns conventional molecular dynamics simulation followed by steered molecular dynamics simulations was performed on the complex with metyrapone. The steered molecular dynamics simulations showed that metyrapone egress via channel 1, threading through the B-C loop, only required a relatively small rupture force and small displacement of residues, whereas egress via the third channel, between helix I and helices F′ and G′, required a relatively large force and perturbation of helices I, B′, and C. The conventional dynamics simulation indicated that channel 2, located between the β1 sheet, B-B′ loop, and F′-G′ region, is closed because of the movement of residues in the mouth of this channel. The findings suggest that channel 1 can be used for metyrapone egress, whereas both channel 2 and channel 3 have a low probability of serving as an exit channel for metyrapone. In addition, residues F108 and I120 appear to act as two gatekeepers to prevent the inhibitor from leaving the active site. These results are in agreement with previous site-directed mutagenesis experiments. The American Society for Pharmacology and Experimental Therapeutics