Investigation of Atrial Natriuretic Peptide as A Competitive Inhibitory Candidate Against Wnt/β-Catenin Signalling: A Molecular Dynamics Approach

Abstract

Wnt/β-catenin signaling, a highly evolutionary conserved pathway, is abnormally regulated in many human cancers. This pathway is one of the proposed mechanisms of atrial natriuretic peptide (ANP) anti-cancer effect. ANP which at first reported as a cardio hormone, inhibits proliferation of different cancer cell lines and tumor growth in vitro and in vivo respectively. Previous studies have shown a possibility of direct interaction between ANP and Frizzled (FZD), the main extracellular receptor of the pathway, and so a competition between ANP and Wnt for binding to this receptor. Here, using a molecular dynamics approach, we investigated this hypothesis validity and also the probable mechanism involved. We found three overlapping binding regions between ANP and Wnt3a carboxyl-terminal domain (CTD) on FZD7, but there is not any overlap with the large amino-terminal domain (NTD) of this protein. Based on the results derived from our study and the previous report on the intrinsic inhibitory potential of NTD subdomain against Wnt signalling and the conserved structure of Wnt-FZD complex architecture, we concluded that ANP is able to compete with Wnt CTD for binding to FZD that it can lead to incompletion of complex formation procedure between Wnt3a and FZD7. Finally, we introduce this peptide as a potential scaffold to design selective inhibitors against FZD-dependant cancers.