Consensus modelling and molecular dynamics studies for the identification of novel telomerase inhibitors as anti-cancer agents

Abstract

Telomerase plays an important role in early stages of life-maintaing telomere and chromosomal integrity of frequently dividing cells. It turns dormant in most somatic cells during adulthood. However, in cancer cells, telomerase gets reactivated and works tirelessly to maintain the length of telomeres, leading to immortality of cells. Hence, in this study, we have used a combined ligand-based and structure based drug design approach for the identification of novel telomerase inhibitors as anti-cancer agents. We have generated ligand-based QSAR models and structure-based pharmacophores models, according our recent MYSHAPE approach (1), and validated exhaustively. The validated models were used for screening our in house database. A total of 200 hits, obtained through various in silico screening techniques, were filtered to 25 compounds using docking studies. Molecular dynamics simulations were carried out to compare the binding mode and stability of the complexes of Telomerase bound to known inhibitors and the top ranked hits. The results obtained in this study gave assurance about the identified hits as prospective inhibitors of telomerase. Selected hits were synthetized and they are currently screened for inhibitory activity.