4
Bioorganic & Medicinal Chemistry Letters
performed. Quercetin (4) was found to display overlapping
interactions exactly like alpha-napthoflavone. Quercetin showed π-π
interactions with Phe 134 and Phe 231. Further, it displayed H-
binding interactions with Asp 326 and Asn 265 residues of the
CYP1B1 binding pocket (Figure 2A). The overlay image of
quercetin with ANF in the binding cavity of CYP1B1 is shown in
supporting information (section S3). In case of glabrol, its terminal
hydroxyl group forms polar H-bond with the Asn 228 residue of F
helix and both phenyl ring forms hydrophobic π-π interactions with
C helix Phe134 and F helix Phe231 residue. The diprenylated rings
showed favorable van der Waals interactions with receptor.
However, despite of common interactions pattern, quercetin (4) and
glabrol (6) displayed difference in inhibition potency towards
CYP3A4 and CYP2D6 which is due to the difference in structural
architecture of these enzymes (i.e. shape and amino acid residues
that form edges of the cavity). In case of CYP2D6, they displayed
only π-π hydrophobic interactions with the Phe483 residue. While in
case of CYP3A4, glabrol interacts with Phe215 residue rather than
corresponding Phe231 residue of CYP1A1 in F helix due to the open
nature of the binding cavity.
Supporting information available. Experimental procedures and
spectral data scans. This material is available free of charge via the
ACKNOWLEDGEMENTS
The work was supported by CSIR 12th FYP grant # BSC-0205 (SBB)
and HEIF funding (BC).
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In summary, we have identified that G. glabra possesses potent
ability to inhibit CYP1B1 and CYP1A1 enzymes, and it protects
cells from procarcinogens and overcomes cisplatin-resistance in
CYP1B1 over-expressing triple negative breast cancer cells MDA-
MB-468. Quercetin, a flavonoid isolated from this plant is also a
potent inhibitor of CYP1B1 and it effectively reverses the cisplatin
resistance in breast cancer cells. These results warrant further
exploration of G. glabra and quercetin as resistance reversal agents
in animal models.