Figure 17. IRC calculations of
the ligand-AB3dendritic-prodrug conjugate.
To investigate changes in interaction energy between various functional
components along the IRC path, we performed GAMESS/FMO calculations at
the M06-2x/6-31+G(d) level. FMO2 calculations were performed for the
seven fragments corresponding to seven functional components in order to
obtain four snapshots along the PES of the R’ state to the TS. Figure 18
shows the interacting/bonding energies of fragments 1-2 and 3-4 remained
similar along the reaction path (~−30.0 Hartree),
although the bonding energies of the linker–drug fragments (5-4, 5-3,
6-4, 6-5, 7-3, and 7-4) showed relatively large fluctuations at
different stages of the reaction pathway. For example, the
interacting/bonding energies of fragments 7-3 and 7-4 were −31.61
Hartree and −15.18 Hartree in R’ (Figure 18a) and −0.01 Hartree and
−52.89 Hartree at the IRC path’s middle point (Figure 18b). For the
spacer–linker fragment (2-3), the interacting/bonding energies were
−29.36 Hartree in R’ (Figure 18a) and −16.16 Hartree during the TS
(Figure 18d). These changes indicated that the drug components in the
ligand-AB3 dendritic-prodrug conjugate were more
flexible and experienced various structural changes relative to the
other components, such as the ligand and spacer. Furthermore, the
C–N(H) bond of spacer–linker fragment 2-3 can undergo heterolytic
dissociation in the presence of a catalyst. According to a previous
study,89 enzymatic cleavage of the bond at Phe–Lys
interaction can trigger dissociation of the conjugate and promote triple
elimination to release the three paclitaxel molecules from each
dendritic platform. Although full-stack calculations have not yet been
performed for the entire therapeutic release mechanism, FMO, combined
with TS calculations, represent a useful tool for studying the
drug-release mechanism.