Docking and molecular dynamics simulations of ORPphilins targeting OSBP

Oxysterol-bind protein (OSBP) mediates cholesterol/phosphatidylinositol-4-phosphate (PI4P) exchange between subcellular compartments, thereby contributing to numerous cellular processes and being linked to several diseases such as cancer and viral infections. Its lipid transfer activity relies on the ORD domain, which forms a hydrophobic pocket enabling binding of sterols and PI4P. Natural compounds from the ORPphilin family have emerged as promising antiviral agents, by targeting the OSBP ORD. However, their functioning at the molecular level remains poorly documented. In this chapter, we detail molecular modelling approaches that offer a valuable tool for exploring these interactions, as they provide dynamic insights into proteinligand complexes not captured by crystallography alone, while being much faster to obtain. With docking and molecular dynamics (MD) simulations methods, one can predict ORPphilin orientations within the ORD pocket, visualize the complexes, and identify specific binding residues, which could serve as basis for designing mutagenesis experiments. MD simulations can further reveal differences in binding energies among ORPphilins, thereby providing mechanistic insights and rationalization of experimental observations.