3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition

被引:55
作者
Alarn, Sarfaraz [1 ,2 ]
Khan, Feroz [1 ,2 ]
机构
[1] CSIR, Cent Inst Med & Aromat Plants, Metab & Struct Biol Dept, PO CIMAP, Lucknow 226015, Uttar Pradesh, India
[2] Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India
关键词
POTENT INHIBITORS; DRUG DESIGN; DERIVATIVES; DISCOVERY; 2-ARYLQUINAZOLIN-4-ONES; POLY(ADP-RIBOSE); IDENTIFICATION; QSAR;
D O I
10.1038/s41598-019-41984-7
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Flavones are known as an inhibitor of tankyrase, a potential drug target of cancer. We here expedited the use of different computational approaches and presented a fast, easy, cost-effective and high throughput screening method to identify flavones analogs as potential tankyrase inhibitors. For this, we developed a field point based (3D-QSAR) quantitative structure-activity relationship model. The developed model showed acceptable predictive and descriptive capability as represented by standard statistical parameters r(2)(0.89) and q(2)(0.67). This model may help to explain SAR data and illustrated the key descriptors which were firmly related with the anticancer activity. Using the QSAR model a dataset of 8000 flavonoids were evaluated to classify the bioactivity, which resulted in the identification of 1480 compounds with the IC(50 )value of less than 5 mu M. Further, these compounds were scrutinized through molecular docking and ADMET risk assessment. Total of 25 compounds identified which further analyzed for drug-likeness, oral bioavailability, synthetic accessibility, lead-likeness, and alerts for PAINS & Brenk. Besides, metabolites of screened compounds were also analyzed for pharmacokinetics compliance. Finally, compounds F2, F3, F8, F11, F13, F20, F21 and F25 with predicted activity (IC50 ) of 1.59, 1, 0.62, 0.79, 3.98, 0.79, 0.63 and 0.64, respectively were find as top hit leads. This study is offering the first example of a computationally-driven tool for prioritization and discovery of novel flavone scaffold for tankyrase receptor affinity with high therapeutic windows.
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页数:15
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