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Exploring Structural Conformations of Human P450 1A1 with Diverse Ligands
Author(s) -
Bart Aaron G.,
Scott Emily E.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.564.1
Subject(s) - chemistry , active site , pharmacophore , stereochemistry , ligand (biochemistry) , cyp3a4 , erlotinib , enzyme , cytochrome p450 , biochemistry , pharmacology , biology , receptor , epidermal growth factor receptor
The human P450 enzyme 1A1 (CYP1A1) is an extrahepatic P450 often expressed in tumor tissues where it may be clinically significant in procarcinogens and toxin bioactivation. Prototypical CYP1A1 ligands are planar and polycyclic aromatic compounds, such as the procarcinogen benzo[a]pyrene found in environmental combustion and tobacco smoke. The single crystal structure of CYP1A1 is with the polycyclic, planar molecule alpha‐napthoflavone (αNF) and reveals a narrow active site that is consistent with planar CYP1A1 ligands. However, a number of known CYP1A1 substrates and inhibitors do not adhere to these typical ligand features, including promising pro‐drugs in cancer therapy based on a duocarmycin scaffold and clinically used tyrosine kinase inhibitors. Such CYP1A1 ligands could not be accommodated in the active site of the CYP1A1/αNF structure. This study aims to determine how CYP1A1 binds atypical CYP1A1 substrates and inhibitors using co‐crystallization. Potential ligands for co‐crystallization trials with CYP1A1 were selected based on structural diversity, focusing on those that are not compatible with the 1A1/αNF crystal structure active site dimensions. Refinement of these ligands was performed by ranking based on their ability to inhibit CYP1A1 metabolism of a pro‐luciferin substrate. Anticancer tyrosine kinase inhibitors (erlotinib, imatinib, and ponatinib) displayed nanomolar to low micromolar IC 50 values. A series of antifungal azoles, which are generally potent P450 inhibitors, resulted in a range of inhibitory responses. Compact, lower MW clotrimazole, miconazole, and tioconazole exhibited sub‐nanomolar potency, but the much larger extended azoles ketoconazole and posaconazole were also potent nanomolar inhibitors. The azoles fluconazole and letrozole were significantly less potent inhibitors with micromolar IC 50 values. The pro‐duocarmycin drug ICT2700 and antitumor benzothiazole GW 610 inhibited CYP1A1 in the sub‐micromolar to nanomolar range. Compounds displaying potent inhibition are being employed in cocrystallization and structure determination. The structural results with atypical CYP1A1 ligands should provide a more robust framework for both prediction of procarcinogen and toxin activation and the development of novel CYP1A1‐activated cancer therapies. Support or Funding Information This work was supported by National Institutes of Health Grants F37 GM076343 (to EES). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .