Molecular Modeling of Interactions of the Benzolactam-V8 Modulators with the Cys2 Domain of Protein Kinase Cδ

Molecular modeling of interactions of four 7‐ or 8‐substituted benzolactam‐V8 (BLV) molecules with the cys2 activator‐binding domain of protein kinase C (PKCδ) was carried out using molecular docking program Autodock. The docked models reveal that the hydroxymethyl group at the C(5) atom of the eight‐membered ring of each BLV is bound at the bottom of the binding groove of the cys2 domain of PKCδ. The BLV molecules make hydrogen bonds and hydrophobic interactions with PKCδ, which are similar to those in the crystal structure of the cys2 domain of PKCδ in complex with phorbol 13‐acetate. BLV‐1 does not contain a long side chain that is hydrophobic and necessary for membrane insertion, so that it would not be a potent modulator of PKCδ. The other three BLV molecules have long side chains substituted at C(7) or C(8) atoms, and it was predicted, based on the docking results, that they had the PKCδ‐binding affinity in the order of BLV‐2>BLV‐4>BLV‐3, and BLV‐2 would be a potent activator of PKCδ.