Application of two-dimensional binary fingerprinting methods for the design of selective Tankyrase I inhibitors

Abstract

In the present study, five important binary fingerprinting techniques were used to model novel flavones for the selective inhibition of Tankyrase I. From the fingerprints used: the fingerprint atom pairs resulted in a statistically significant 2D QSAR model using a kernel-based partial least square regression method. This model indicates that the presence of electron-donating groups positively contributes to activity, whereas the presence of electron withdrawing groups negatively contributes to activity. This model could be used to develop more potent as well as selective analogues for the inhibition of Tankyrase I. Schematic representation of 2D QSAR work flow.

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

“…Recently, both 2D-and 3D-quantitative structure− activity relationship (QSAR) models have been engaged for the discovery of new flavone-based tankyrase inhibitors. 149,150 Collectively, the above studies have laid the foundation for the rational use of flavone as a chemical scaffold for tankyrase inhibitors and have also guided the development of other analogous structures. A good example of the latter is 2phenylquinazolin-4-one, which was further modified into tankyrase/kinase dual inhibitors.…”

“…Crystals of tankyrase 2 in complex with the majority of active flavones were successfully grown and analyzed, unveiling a common binding pattern: (i) the keto oxygen atom of the chromen-4-one core makes hydrogen bonds with the backbone amide of G1032 and the hydroxy side chain of S1068 and (ii) the pyran ring forms a π–π stacking interaction with the aromatic side chain of Y1071 (Figure E). , In addition, various substituents on the flavone scaffold develop further interactions with the enzyme directly or through water molecules. Recently, both 2D- and 3D-quantitative structure–activity relationship (QSAR) models have been engaged for the discovery of new flavone-based tankyrase inhibitors. , Collectively, the above studies have laid the foundation for the rational use of flavone as a chemical scaffold for tankyrase inhibitors and have also guided the development of other analogous structures. A good example of the latter is 2-phenylquinazolin-4-one, which was further modified into tankyrase/kinase dual inhibitors. , Another natural product investigated as a tankyrase inhibitor is magnolol, but research into this skeleton is still very much in its infancy; only a few synthetic magnolol derivatives were found to have an affinity for tankyrase 2 …”

Fingerprint Based Two-dimensional QSAR Studies on Pyrazolo Quinazolines as Cdk2 Inhibitors: A Rational Approach for the Design of Novel Anticancer Agents

“…Description: pairs of atoms is segregated by the type and distance separating them. 27 The fingerprint decides the principle of atom pairs (pairs of atoms) and the distance separating them: Type a -Type b -d ab where, Type a ≤ Type b . The representation is hashed into an integer value and 'd' is the shortest distance between any pair of atoms.…”