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Aurora kinase A has been emerging as a key therapeutic target for the design of anticancer drugs. For the purpose of finding biologically active and novel compounds and providing new ideas for drug-design, we performed virtual screening using commercially available databases. A three-dimensional common feature pharmacophore model was developed with the HipHop program provided in the Catalyst software package, and this model was used as a query for screening the databases. A recursive partitioning (RP) model was developed as a filtering system, which was able to classify active and inactive compounds. Eventually, a step-wise virtual screening procedure was conducted by applying the common feature pharmacophore and the RP model in succession to discover novel potent Aurora-A inhibitors. A total of 68 compounds were selected for testing of their in vitro anticancer activities against various human cancer cell lines. Based on the activity data, we have identified fifteen compounds that warrant further investigation. Several compounds have a high inhibition rate (above 80% at 10 μM) and a GI₅₀ lower than 5 μM for the cell lines DU145 and HT29. Enzyme assay for these compounds identified hits with micro molar activity. Compound C11 has the highest activity (IC₅₀ = 5.09 μM). The hits obtained from this screening scheme could be potential drug candidates after further optimization., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure-activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R(2)(CV) = 0.58, R(2) = 0.82 and r(2)(pred) = 0.62) and the comparative molecular similarity index analysis (R(2)(CV) = 0.74, R(2) = 0.98 and r(2)(pred) = 0.81) gave reasonable results. Besides pharmacophore-based alignment, the maximum common substructure-based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore-based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H-bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.