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

Abstract

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.

How Ligands Interact with the Kinase Hinge

“…Briefly, the Fs-IFP method comprises three steps. The first step aligns the ligand-binding sites using a sequence order-independent strategy (SMAP). , The second step converts all the 3D binding site-ligand interaction information into a 1D bit-string representation by encoding molecular interaction fingerprints (IFPs). − The IFPs are generated based upon a set of predefined geometric rules (see the Supporting Information) that classify residue-based interactions into seven types: hydrophobic, aromatic (face-to-face), aromatic (edge-to-face), H-bond (protein as donor), H-bond (protein as acceptor), electrostatic (protein positively charged), and electrostatic (protein negatively charged) using the software IChem. , Thus, every residue-ligand interaction is represented by a seven-bit string (Supporting Information), for example, “0001000” where “1” indicates the interaction exists between this residue and ligand, and its fourth position in the seven-bit string shows the interaction is an H-bond (protein as donor). In contrast, “0” means the ligand has no interaction with this residue.…”

How Ligands Interact with the Kinase Hinge

“…The second step converts all the 3D binding siteligand interaction information into a 1D bit-string representation by encoding molecular interaction fingerprints (IFPs). [39][40][41] The IFPs are generated based upon a set of predefined geometric rules that classify residue-based interactions into seven types: hydrophobic, aromatic (face-to-face), aromatic (edge-to-face), H-bond (protein as donor), H-bond (protein as acceptor), electrostatic (protein positively charged), and electrostatic (protein negatively charged). 39 Thus, 6 every residue-ligand interaction is represented by a seven-bit string, for example, "0001000" where "1" indicates the interaction exists between this residue and ligand, and its fourth position in the seven-bit string shows the interaction is an H-bond (protein as donor).…”