CHA on CDK2: a way to identify the best pharmacophore model for the virtual screening of new inhibitors

Cyclin-dependent kinase-2 (CDK2) is a member of serine/threonine protein kinases family. It plays an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidences indicate that excessive expression of CDK2 should cause abnormal cell cycle regulation. Therefore, CDK2 has been considered a potential therapeutic target for cancer therapy. In this work, we used a modelling approach that incorporates flexibility based on extensive MD simulations of protein−ligand complexes into structure-based pharmacophore modeling and virtual screening to identify new CDK2 inhibitors. One-hundred and forty-nine CDK2-inhibit…

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

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 use…

Integrated computational and experimental approaches for the identification of new molecules with readthrough activity on premature termination codons (PTCs) in cystic fibrosis cells

Novel molecules for the readthrough of PTCs in biological model systems and in cystic fibrosis cells

Optimization of a new lead promoting the readthrough of the nonsense mutations for CFTR rescue in human CF cells

Optimization of a new lead promoting the readthrough of the nonsense mutations for CFTR rescue in human CF cells Laura Lentini, Raffaella Melfi, Sara Baldassano, Marco Tutone, Aldo Di Leonardo, Andrea Pace, Ivana Pibiri Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo Background and rationale Cystic Fibrosis patients with nonsense mutations in the CFTR gene have a more severe form of the disease. Nonsense mutations represent about 10% of the mutations that affect the CFTR gene and they are frequently associated to the classical F508 mutation (1). A potential treatment for this genetic alteration is to promote the translationa…

Natural bioactive molecules induce a reduction of surface alpha-enolase in breast cancer cells

Cell surface expression of alpha-enolase, a glycolytic enzyme displaying moonlighting activities, has been shown to contribute to cancer cell invasion and metastasis formation. Although the functional role of surface alpha-enolase in cancer spreading has been clearly linked to the protein non-enzymatic function of binding plasminogen and enhancing plasmin formation, the cellular pathways underlying cell surface transport remain largely elusive. We have previously demonstrated that pro-invasive stimuli promote the surface expression of alpha-enolase in breast cancer cells. To further investigate alpha-enolase translocation to the plasma membrane and to identify the signaling involved in this…

Translational Readthrough Inducing Drugs (TRIDs): a study of biodistribution evaluation in mice models