Molecular mechanism of the interaction between BCL2 and sonrotoclax. (A) Overview of the structure of BCL2 in complex with sonrotoclax. The protein is shown as an electrostatic surface, with the compound shown in yellow. (B) Binding details of sonrotoclax. Water molecules are shown as red spheres. Hydrogen bonds are represented by green dashed lines. (C) Superimposition of the structures of BCL2 in complex with sonrotoclax (yellow stick) and venetoclax (cyan stick, protein shown as pink ribbon, PDB ID: 6O0K). (D) Zoomed in view of the superimposed structures shown in panel C. The F112 residues underneath the P2 pocket are shown as purple and pink sticks. (E) Comparison of the occupation of the P2 pocket by venetoclax (cyan stick) and sonrotoclax. The subpocket is indicated by a red arrow. (F) Zoomed in view of the binding details of the (S)-2-(2-isopropylphenyl)pyrrolidine moiety. The subpocket is encircled by a light orange dashed line, and the sulfonyl-π and π-π interactions are indicated by purple dashed lines.