posted on 2023-12-28, 03:06authored byKecheng Yang, Hongmin Liu
Lysine-specific demethylase 1 (LSD1)
is a promising therapeutic
target for cancer therapy. So far, over 80 crystal structures of LSD1
in different complex states have been deposited in the Protein Data
Bank, which are valuable resources for performing structure-based
drug design. However, among all of the crystal structures of LSD1,
the substrate binding pocket, which is the most efficient druggable
site for designing LSD1 inhibitors at present, is very similar no
matter whether LSD1 is in the apo or any holo forms, which is inconsistent
with its versatile demethylase functions. To investigate whether the
substrate binding pocket is rigid or exhibits other representative
conformations different from the crystal conformations that are feasible
for designing new LSD1 inhibitors, we performed funnel metadynamics
simulations to study the conformation dynamics of LSD1 in the binding
process of two effective LSD1 inhibitors (CC-90011 and 6X0, CC-90011
undergoing clinical trials). Our results showed that the entrance
of the substrate binding pocket is very flexible. Two representative
entrance conformations of LSD1 counting against binding with the substrate
of histone H3 were detected, which may be used for structure-based
LSD1 inhibitor design. Besides, alternative optimal binding modes
and prebinding modes for both inhibitors were also detected, which
depicted that the key interactions changed along with the binding
process. Our results should provide great help for LSD1 inhibitor
design.