Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening

Abstract

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure- activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc 'clean drug-like' database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.

Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model

“…To construct the general pharmacophore model, we used known inhibitors of various serine-threonine kinases published in scientific literature and found in the ASINEX proprietary collection. Published STPK inhibitors included inhibitors of tuberculosis kinases, mTor kinase, Aurora A and B kinases, as well as B-Raf kinases [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. ASINEX proprietary collections included novel compounds tested and found to be active against pknA, pknB kinases.…”

“…A number of attempts have been made to construct a pharmacophore model for various Ser/Thr kinase inhibitors, such as serine/threonine receptor kinase (STPK) inhibitors of tuberculosis, mTor kinase inhibitors, Aurora A and B inhibitors, B-Raf inhibitors, etc. [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Some of these models are based on the structure-based approach, i.e.…”

“…This results in “double step prediction”: first the modeling of the binding site is done, followed by docking, which in turn decreases the obtained hit rate. Another group of these models has been developed based on the ligand-based approach [ 4 , 5 , 6 , 7 , 8 ]. In general, a more- or less-wide group of molecules is to be aligned and the common structure features are elucidated.…”

“…In general, a more- or less-wide group of molecules is to be aligned and the common structure features are elucidated. Usually, common structure features are developed into more general pharmacophore models [ 4 , 5 , 6 , 7 ].…”

Identification of a thienopyrimidine derivatives target by a kinome and chemical biology approach

“…Four of the thienopyrimidine analogues (5a-5d) exhibited good inhibitory activity against FLT3 (IC 50 range from 0.055 to 0.208 lM) with similar or improved activities compared to AC220, a selective FLT3 inhibitor (IC 50 = 0.120 lM). In addition to the kinase Paper Discovery of a novel series of thienopyrimidine as highly potent and selective PI3K inhibitors (Han et al 2015) mTOR/PI3Ka Paper Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTORa/ PI3Ka inhibitors (Zhu et al 2015) EGFR Paper Truncated structures used in search for new lead compounds and in a retrospective analysis of thienopyrimidine-abased EGFR inhibitors (Bugge et al 2015) Aurora A Paper Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening (Chavan et al 2014) Aurora B Paper A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting aurora B kinase activity (Li et al 2013) ErbB2…”