Structure-based virtual screening to identify novel carnitine acetyltransferase activators

Abstract

Carnitine acetyltransferase (CAT) is an attractive therapeutic target against fibrosis. We have identified few CAT activators through structure-based virtual screening followed by molecular dynamics simulations for assessment of the binding mode. A set of 10,000 drug-like molecules properly filtered from an initial chemical library of 13 M commercially available compounds were docked into the active site. Virtual hits were selected for in vitro experimental testing to validate the computational findings and the stability of the predicted complexes was evaluated by molecular dynamics simulations. Applied protocol led to the identification of three hit compounds showing promising activity, which can serve as potential scaffolds for further structural optimization. This is the first report of successful discovery of CAT activators through the use of structure-based virtual screening.

Keywords: Curcumin; Fibrosis; Molecular docking; Molecular dynamics simulations; Virtual hits.