Identification of Novel CDK2 Inhibitors by QSAR and Virtual Screening Procedures

Abstract

Quantitative Structure -Activity Relationship (QSAR) studies were carried out on a set of 46 imidazo[1,2-a]pyridines, imidazo[1,2-b]pyridazines and 2,4-bis anilino pyrimidines, and nitroso-6-aminopyrimidine and 2,6-diaminopyrimidine inhibitors of CDK2 (Cyclin-dependent Kinase2) using a multiple regression procedure. The activity contributions of these compounds were determined from regression equation and the validation procedures such as external set cross-validation r 2 , (R 2 cv,ext ) and the regression of observed activities against predicted activities and vice versa for validation set were described to analyze the predictive ability of the QSAR model. An accurate and reliable QSAR model involving five descriptors was chosen based on the FIT Kubinyi function which defines the statistical quality of the model. The proposed model due to its high predictive ability was utilized to screen similar repertoire of compounds reported in the literature, and the biological activities are estimated. The screening study clearly demonstrated that the strategy presented shall be used as an alternative to the time-consuming experiments as the model tolerated a variety of structural modifications signifying its potential for drug design studies.

The synthesis of potential DNA intercalators. 3†. Triazanaphthalene, tetraaza anthracene and phenanthrene from isoxazolones

“…Since imidazo[1,2-a]azaheterocycles such as those in Scheme 3 above may be converted to larger heterocycles that can be expected to intercalate with DNA because of their H-bonding donor and acceptor groups, [8][9][10] this work was extended to bis-isoxazolinyl diazaheterocycles. 2 Structures 1, 2, and 4 are clearly well set up as precursors for polycyclic structures which are of considerable interest as pharmacophores for therapeutic drugs.…”

A Study of CDK2 Inhibitors Using a Novel 3D‐QSAR Method Exploiting Receptor Flexibility

“…As a result many different chemical scaffolds have been investigated, including, e.g., pyrazoles [1 -4], indirubins [5], and a number of pyrimidine-based inhibitors [6 -11]. The literature contains several QSAR models of various CDK2 inhibitors such as oxindoles [12], purines [13], and pyrimidines [14], yet none of these have considered the effects of receptor flexibility in the building of QSAR models.…”

Pyridazine Chemistry in Crop Protection

“…The process in the preparative investigations on pyridazines has been summarized periodically in exhaustive reviews . Also, the activity of pyridazine derivatives in the field of analgesics and inflammation , antibiotics , epilepsy , cardiovascular diseases , and oncology has been reviewed recently. The only heterocyclic scaffolds, for which so far extensive reviews exist regarding their significance in crop protection chemistry, are pyrazole , pyridine , pyrimidine , thiazole , and isothiazole .…”