High-throughput virtual screening of novel potent inhibitor(s) for Human Vanin-1 enzyme

Vanin-1 (VNN1) is a glycosylphosphatidylinositol (GPI)-anchored ectoenzyme which hydrolyzes pantetheine to pantothenic acid and cysteamine. It has emerged as a promising drug target for many human diseases associated with oxidative stress and inflammatory pathways. In the present study we used structure-based virtual screening approach for the identification of small molecule inhibitors of vanin-1. A chemical library consisting of natural compounds, synthetic compounds and RRV analogs were screened for drug-like molecules. The filtered molecules were subjected to molecular docking studies. Three potential hits-ZINC04073864 (Natural compound), CID227017 (synthetic compound) and CID129558381 (RRV analog)-were identified for the target enzyme. The molecules form good number of hydrogen bonds with the catalytic residues such as Glu79, Lys178 and Cys211. The apo-VNN1 and VNN1-ligand complexes were subjected to molecular dynamics (MD) simulation for 30 ns. The geometric properties such as root mean square deviation, radius of gyration, solvent accessible surface area, number of hydrogen bonds and the distance between the catalytic triad residues-Glu79, Lys178 and Cys211 were altered upon binding of the compounds. Essential dynamics and entropic studies further confirmed that the fluctuations in VNN1 decrease upon binding of the compounds. The lead molecules were stable throughout the simulation time period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) studies showed that Van der Waals interaction energy contributes significantly to the total binding free energy. Thus, our study reveals three lead molecules-ZINC04073864, CID227017 and CID129558381 as potential inhibitors of Vanin-1 which can be validated through further studies. Communicated by Ramaswamy H. Sarma

Automated summary

This study used a structure-based virtual screening approach to identify potential inhibitors of Vanin-1. Three lead molecules were found to form hydrogen bonds with catalytic residues and cause alterations in the enzyme's geometric properties. Molecular dynamics simulation showed that the lead molecules reduced the fluctuations in Vanin-1 and remained stable throughout the simulation period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) studies indicated that van der Waals interaction energy significantly contributed to the binding free energy. These findings suggest that the lead molecules could serve as potential inhibitors of Vanin-1 for further investigation.