In Silico Study Of Interaction Between Potentiator Glpg1837 And Cystic Fibrosis Chloride Ion Channel

Abstract

Cystic fibrosis (CF) disease is a lethal genetic disease that causes persistent lung infections, limits the ability to breathe, and significantly reduce the life expectancy. In CF patients, mutations at cystic fibrosis transmembrane conductance regulator (CFTR) make the CFTR become dysfunctional, leading to little or none chloride ion transportation to outside the cell. Among many loss-of-function mutations of CFTR protein, G551D, the third most common one, has been characterized as having a lower open probability (Po) than wild-type (WT) channels. Currently, a novel investigational compound named GLPG1837 is proved to be double more efficacious than the commercial drug Ivacaftor (VX-770) and do not interfere with CFTR stability in vitro experiments, but its affinity and mechanism have not been well studied yet. This study reveals molecular insight into the effect of GLPG1837 on CFTR protein by using molecular docking and targeted molecular dynamics (TMD) simulation. The results proposed the same binding site but different mechanism of GLPG1837 to the commercial one on a revised CFTR model particularly, the stimulating effect of GLPG1837 on the first stage of the mutant channel gating process. Our data confirmed the stronger effect of GLPG1837 than VX-770 in a small perspective of in silico study, which contributes to the development of more potent modalities correcting the effects of CFTR mutations.