title: Probing possible egress channels for multiple ligands in human CYP3A4: a molecular modeling study.
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.
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 program), Environmental Biotechnology National Core Research Center, Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, Jinju, 660-701, Korea.
authors.forename: Navaneethakrishnan
authors.initials: N
authors.lastname: Krishnamoorthy
authors.forename: Poornima
authors.initials: P
authors.lastname: Gajendrarao
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Yuno
authors.initials: Y
authors.lastname: Lee
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D007654:Ketoconazole / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D008024:Ligands; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole