Equilibrium binding dynamics is studied for a panel of benzimidazole-containing compounds at the remodeled interface between human growth hormone (hGH) and the extracellular domain of its receptor (hGHbp), engineered by mutating to glycine hot spot residues T175 from the hormone and W104 from the receptor. Binding energetics is predicted in a good agreement with the experimental data for a panel of these small molecules that complement the engineered defect and restore the binding affinity of the wild-type hGH-hGHbp complex. The results of simulated tempering ligand dynamics at the protein-protein interface reveals a diversity of ligand binding modes that is consistent with the structural orientation of the benzimidazole ring which closely mimics the position of the mutated W104 hot spot residue in the wild-type hGH-hGHbp complex. This structural positioning of the benzimidazole core motif is shown to be a critical feature of the low-energy ligand conformations binding in the engineered cavity. The binding free energy analysis provides a plausible rationale behind the experimental dissociation constants and suggests a key role of ligand-protein van der Waals interactions in restoring binding affinity.