Background: The water insolubility of fullerene C60 nanostructure greatly hampers its
biological applications as an effective HIV-1 protease inhibitor, which suggests to synthesis new C60
derivatives with different functional polar groups.
Method: The new carbon nanostructures of fulleropyrrolidines with one and two polar acetoxyhydroxyl
(AcH) groups (C60-A and C60-B, respectively) were constructed to evaluate their interactions
and binding affinity into HIV-1 protease active site via theoretical molecular docking and molecular
dynamic simulations. Data obviously indicated the higher affinity of fulleropyrrolidines derivatives
C60-A and C60-B compared to fullerene C60 in interacting with HIV-1 protease active site cavity. The
functional groups in C60 caused better residing of C60 derivatives in the center of active site by
changing the spherical shape of C60, constructing different stable H-bonds with supporting the main π
interactions between C60 and aromatic Phe53/Arg8 in protease active site. Our finding showed that the
functionalization of C60 is essential for both increasing solubility and improving different π interactions
of C60 with protease. Also, H-bond forming with AcH functional groups and enzyme active site
residues is more important to support the van der Waals interactions between C60 fragment of
fulleropyrrolidines and enzyme cavity. Since enzyme possesses aspartic acid residues in active site,
C60-B with two AcH groups interacted with the active site more efficiently via additional H-bond
relative to C60-A.
Results: Finally, the results indicate a possible use of the investigated fulleropyrrolidines derivatives as
new HIV-1 protease inhibitors.