RT Journal Article
SR Electronic
T1 Molecular Modeling Suggests Homologous 2-APB Binding Sites in Connexins 26 and 32
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 287326
DO 10.1101/287326
A1 Thomas W. Comollo
YR 2018
UL http://biorxiv.org/content/early/2018/03/23/287326.abstract
AB Connexins are the transmembrane pore forming proteins that participate in gap junctions; connections between cells that certain nutrients and other molecules can pass through. There are several kinds of connexins (Cx) named based on their weight in kilodaltons. 2-aminoethoxydiphenyl borate (2-APB) is a small molecule inhibitor (SMI) of Cx26 and Cx32. Knock out of Cx32 and also blockage of Cx32 by 2-aminoethoxydiphenyl (2-APB) has been suspected to be beneficial in not only, drug induced liver toxicity, but also in blocking the propagation of an inflammatory signal. If the binding site of 2-APB can be determined, virtual screening for additional, perhaps more specific Cx26 and Cx32 blocking SMI can be carried out. Our modeling suggests that 2-APB binds to similar sites inside the pores of Cx26 and Cx32. Here 2-APB interacts with the conserved ILE82 and THR86. These residues hold the same numbering in both CX26 and CX32. This suggests these residues have a high level of conservation and importance Further virtual screening results imply molecules with similar activity on Cx26 and Cx32 as 2-APB can be found.Background 2-APB has been shown to block Cx26 and Cx32.Results Docking of 2-APB to Cx26 and CX32 finds conserved binding site in pore. Suggestive that 2-APB has conserved homologous binding site on Cx26 and Cx32.Conclusion Mutational studies of 2APB and ILE82 and THR86 in Cx26 and Cx32 appear warranted. Additional virtual screening could yield 2-APB analogs that act on Cx26 and Cx32.Significance Potential for developing gap junction blocking compounds.