Deep analysis of N-cadherin/ADH-1 interaction: a computational survey

Abstract

Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.

Telmisartan anti‐cancer activities mechanism through targeting N‐cadherin by mimicking ADH‐1 function

“…In fact N-cadherin contribution on generation of cell-cell junctions is less than that of E-cadherin, and its higher expression in PC3 cells is closely related to 'more mesenchymal phenotype' and increased cell invasion capacity of these cells compared with DU145 cells. 37 Based on our previous in silico studies, 15,16 we hypothesized that Tel could act as N-cadherin antagonist. Therefore, in contrast to DU145 of Tel on N-cadherin inhibition.…”

“…13 In previous in silico studies, after deep analysis of N-cadherin/ADH-1 interaction, we screened for FDA-approved small molecules which can act as potential inhibitors for N-cadherin protein. 15,16 Among seven screened candidate drugs, we decided to use one of these inhibitors, Telmisartan (Tel) in the current study. Our hypothesis was that Tel prevents cell migration and inhibits attachment of PCa and breast cancer cells to recombinant N-cadherin coated wells by suppressing N-cadherin.…”

“…Therefore, the use of new drugs with less invasiveness administration route, controllability and high bioavailability is very efficient 13 . In previous in silico studies, after deep analysis of N‐cadherin/ADH‐1 interaction, we screened for FDA‐approved small molecules which can act as potential inhibitors for N‐cadherin protein 15,16 . Among seven screened candidate drugs, we decided to use one of these inhibitors, Telmisartan (Tel) in the current study.…”

Development and application of an agent‐based model for the simulation of the extravasation process of circulating tumor cells

“…Finally, it should be mentioned that several simulation studies using the molecular‐dynamics (MD) technique were carried out with focus on the molecular processes underlying metastasis. Examples are simulation studies investigating the binding process between the P2Y receptor and various adenosine compounds 29,30 or between the N‐cadherin antagonists and N‐cadherin 31 . However, to our knowledge no computational modeling approaches are available up to now, which are able to describe the platelet‐assisted extravasation process of CTCs in its entirety.…”

“…Examples are simulation studies investigating the binding process between the P2Y receptor and various adenosine compounds 29,30 or between the N-cadherin antagonists and Ncadherin. 31 However, to our knowledge no computational modeling approaches are available up to now, which are able to describe the platelet-assisted extravasation process of CTCs in its entirety.…”