Molecular docking and 3D-QSAR-based virtual screening of flavonoids as potential aromatase inhibitors against estrogen-dependent breast cancer.
Aromatase, catalyzing final step of estrogen biosynthesis, is considered a key target for the development of drug against estrogen-dependent breast cancer (EDBC). Identification and development of naturally occurring compounds, such as flavonoids, as drugs against EDBC is in demand due to their lesser toxicity when compared to those of synthetic ones. Thus, a three-dimensional quantitative structure-activity relationship, using comparative molecular field analysis (CoMFA) was done on a series of 45 flavonoids against human aromatase. A significant cross-validated correlation coefficient (q(2)) of 0.827 was obtained. The best predictive CoMFA model explaining the biological activity of the training and test sets with correlation coefficient values (r(2)) of 0.916 and 0.710, respectively, when used for virtual screening of a flavanoids database following molecular docking revealed a flavanone namely, 7-hydroxyflavanone beta-D-glucopyranoside showing highest predicted activity of 1.09 μM. In comparison to a well-established inhibitor of aromatase, namely 7-hydroxyflavanone (IC50: 3.8 μM), the derivative identified in the present study, namely 7-hydroxyflavanone beta-D-glucopyranoside exhibited about 3.5 folds higher inhibitory activity against aromatase. The result of virtual screening was further validated using molecular dynamics (MD) simulation analysis. Thus, a 25 ns MD simulation analysis revealed high stability and effective binding of 7-hydroxyflavanone beta-D-glucopyranoside within the active site of aromatase. To the best of our knowledge, this is the first report of CoMFA-based QSAR model for virtual screening of flavonoids as inhibitors of aromatase.
a Department of Biochemistry, Bioinformatics Infrastructure Facility, Centre of Excellence in Bioinformatics , University of Lucknow , Lucknow 226007 , Uttar Pradesh , India.
Manika
M
Awasthi
Swati
S
Singh
Veda P
VP
Pandey
Upendra N
UN
Dwivedi
D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry*; D047072:Aromatase Inhibitors / Q000737:chemistry*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D005260:Female; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D005419:Flavonoids
3D-QSAR; 7-hydroxyflavanone beta-D-glucopyranoside; aromatase; breast cancer; flavonoids; molecular dynamics simulation