Unraveling fiscalin derivatives' interactions with P-glycoprotein: a computational study

Abstract

Background: P-glycoprotein (P-gp), a crucial efflux transporter located on the apical membrane of vital barrier tissues, plays a critical role in the detoxification of several endobiotics and xenobiotics [1,2]. Notably, fiscalin derivatives exhibit diverse interactions with P-gp, demonstrating inhibitory or activating effects. This interaction leads to a reduction or increase in the transported substrate levels, respectively [3]. Objective: The aim of this study was to elucidate, in silico, the P-gp binding sites and interactions of different fiscalin derivatives. Methods: Molecular Operating Environment (MOE) software was used to build all the energy minimized small-molecules 3D-structures, and Autodock Vina was used to perform the molecular docking to estimate the binding affinity between fiscalins and two human P-gp models [4,5] [at the drug-binding pocket (DBP) and nucleotide binding domains (NBDs) 1 and 2]. The best ranked poses were visualized and the interactions of the ligands with specific P-gp residues were analyzed using the BINANA software. Results: Molecular docking analysis unveiled a notable preference of fiscalins for binding to DBP, where all the ligands bind to residues located in the modulators (M)-site. Additionally, the assessment of interactions between fiscalins and P-gp residues within NBD1 and NBD2 revealed potential novel binding sites. Across these three locations, fiscalins exhibited binding to specific P-gp residues, establishing shared hydrophobic contacts and other significant interactions, including hydrogen-bonds; pi-pi, t-stacking and cation-pi interactions; and salt bridges. Conclusions: The present study confirmed the ability of fiscalin derivatives to bind to P-gp, especially at the M-site of the DBP, as well as at both NBDs. The identified binding interactions may potentially be involved in the fiscalins-mediated P-gp activation.