Computational modeling of small molecule ligand binding interactions and affinities

Understanding and controlling biological phenomena via structure-based drug screening efforts often critically rely on accurate description of protein–ligand interactions. However, most of the currently available computational techniques are affected by severe deficiencies in both protein and ligand conformational sampling as well as in the scoring of the obtained docking solutions. To overcome these limitations, we have recently developed MedusaDock, a novel docking methodology, which simultaneously models ligand and receptor flexibility. Coupled with MedusaScore, a physical force field-based scoring function that accounts for the protein–ligand interaction energy, MedusaDock, has reported the highest success rate in the CSAR 2011 exercise. Here, we present a standard computational protocol to evaluate the binding properties of the two enantiomers of the non-selective β-blocker propanolol in the β2 adrenergic receptor’s binding site. We describe details of our protocol, which have been successfully applied to several other targets.