Molecular modelling studies on cinnoline-based BTK inhibitors using docking and structure-based 3D-QSAR.

BTK inhibitors have been proved as an effective target for B-cell malignancies. Ibrutinib is the most advanced irreversible BTK inhibitor for treating mantle cell lymphoma/chronic lymphocytic leukaemia but with existing drug resistance and adverse effects. To design novel effective and safety reversible BTK inhibitors, 115 newly cinnoline analogues were selected to perform molecular docking and 3D-QSAR study because of the main scaffold similarity to Ibrutinib. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions are preferred at R1 and R3 positions, and introducing hydrophilic and negative electrostatic substitutions at R1 positions is important for improving BTK inhibitory activities. These results will be useful to provide clues for rationally designing novel and high potency BTK inhibitors.