Activation mechanism of claudin-4 by ephrin type-A receptor 2: a molecular dynamics approach.

Claudin-4 is a crucial component in the tight junction which is involved in the organization of a cellular barrier. Claudin-4 is found to be up-regulated in various malignancies and is activated by forming a complex with an ephrin A2 receptor. In this computational study, we propose a rational model for the claudin-4-ephrinA2 complex which is in agreement with the experimental result. The complex model has been obtained through protein-protein docking, interface residue scanning, in silico alanine mutations and extensive molecular dynamics simulations. The docking model envisages the important residues present in the first extracellular loop of claudin-4 that plays an active role in protein-protein interaction and stability. A 30 nanosecond molecular dynamics simulation of the complex revealed a higher stability by which the number of hydrogen bond interactions increased in the complex interface. Both the molecular dynamics simulations and in silico alanine mutations revealed the involvement of Lys65 (claudin-4) as one of the prime residues in the complex interface that is actively engaged in the binding mechanism with its counterpart. We postulate that the novel hotspot, Lys65 of claudin-4 can be targeted through structure based inhibitor design, which could alter the effect of the claudin-4-ephrinA2 binding mechanism in aggressive metastatic tumors.

From natural products to drugs for epimutation computer-aided drug design.

The epimutational event, i.e., ectopic methylation in tumor suppressor genes, can lead to gene silencing, thus promoting prognosis of cancer. The progression of DNA methylation is a cycle of demethylation, de novo methylation, and maintenance methylation. The enzyme responsible for maintenance of methylation status is DNA methyltransferase 1 (DNMT1), the continuous activity of which is required to maintain the pattern of epimutation; thus, its inhibition is a promising strategy for the treatment of cancer. To the best of our knowledge, this study is the first to focus on the recently developed crystal structure of the catalytic site of DNMT1. Here in this study, we have used the crystal structure for the development of non-nucleoside DNMT1 inhibitors using virtual screening (VS), absorption, distribution, metabolism, elimination/toxicology analysis, and molecular docking studies. In this study, VS was carried out on 48,531 natural products to create a subset of lead-like natural products. Three of them were found to form hydrogen bonds with the catalytic site of the DNMT1 (Cys 1226). Thus, this study adumbrates potential lead compounds for treatment of epimutation.