Characterizing the Cooperative Effect of PROTAC Systems with End-Point Binding Free Energy Calculation

Proteolytic targeting chimeras (PROTACs), as an emerging
type of
drug, function by proximity-based modalities that narrow the distance
between a target protein and the E3 ubiquitin ligase to facilitate
the ubiquitination labeling of the target protein for degradation.
Although it is evidenced that the cooperativity of the PROTAC ternary
interaction is one of the key factors affecting the degradation rate
of a target protein, PROTAC design utilizing this indicator is still
challenging because of the complicated/flexible interactions in a
target–PROTAC–E3 ternary system. Therefore, developing
reliable and practicable computational methods is of great interest
for PROTAC design. Hence, in this study, we investigate the feasibility
of using the end-point binding free energy calculation method, represented
by molecular mechanics/Poisson–Boltzmann (generalized-Born)
surface area (MM/PB(GB)SA), for characterizing cooperativity (including
the stabilization and hook effects) of the PROTAC systems. The result
shows that MM/GBSA is a good predictor in characterizing these effects
under a relatively long molecular dynamics adjustment (50–100
ns) and low dielectric constant (εin = 1), with the
Pearson correlation coefficient (rp) >
0.5 and 0.6 for the stabilization and hook effect, respectively. This
study provides a feasible strategy for characterizing the cooperativity
of the PROTAC systems, facilitating the rational design of PROTAC
molecules.