Analysis of KRAS–Ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

KRAS, a common human oncogene, has been recognized as
a critical
drug target in treating multiple cancers. After four decades of effort,
one allosteric KRAS drug (Sotorasib) has been approved, inspiring
more KRAS-targeted drug research. Here, we provide the features of
KRAS binding pockets and ligand-binding characteristics of KRAS complexes
using a structural systems pharmacology approach. Three distinct binding
sites (conserved nucleotide-binding site, shallow Switch-I/II pocket,
and allosteric Switch-II/α3 pocket) are characterized. Ligand-binding
features are determined based on encoded KRAS–inhibitor interaction
fingerprints. Finally, the flexibility of the three distinct binding
sites to accommodate different potential ligands, based on MD simulation,
is discussed. Collectively, these findings are intended to facilitate
rational KRAS drug design.