A molecular docking exploration of the large extracellular loop of tetraspanin CD81 with small molecules

Tetraspanin CD81 is a transmembrane protein used as a co-receptor by different viruses and implicated in some cancer and inflammatory diseases. The design of therapeutic small molecules targeting CD81 lags behind monoclonal antibodies and peptides but different synthetic and natural products binding to CD81 have been identified. We have investigated the interaction between synthetic compounds and CD81, considering both the cholesterol-bound full-length receptor and a truncated protein corresponding to the large extracellular loop (LEL) of the tetraspanin. They represent the closed and open conformations of the protein, respectively. Stable complexes were characterized with bi-aryl compounds (notably the quinolinone-benzothiazole 6) and atypical molecules bearing a 1-amino-boraadamantane scaffold well adapted to interact with CD81 (5a-d). In each case, the mode of binding to CD81 was analyzed, the binding sites identified and the molecular contacts determined. The narrow intra-LEL binding site of CD81 can accommodate the elongated bi-aryl 6 but not a series of isosteric compounds with a bis(bicyclic) scaffold. The bora-adamantane derivatives appeared to bind well to CD81, but essentially to the external surface of the protein loop. The binding selectivity of the compounds was assessed comparing binding to the LEL of tetraspanins CD81, CD9 and Tspan15. A net preference for CD81 over CD9 was evidenced, but the LEL of Tspan15 also provided a suitable binding site for the compounds, notably for the bora-adamantane derivatives. This work provides an aid to the identification and design of tetraspanin-binding small molecules, underlining the distinct behavior of the open and closed conformation of the protein for drug binding.

The online version contains supplementary material available at 10.1007/s40203-024-00203-6.