Abstract
Aim: CDK4/6 have critical roles in the early stage of the cell cycle. CDK2 acts later in the cell cycle and has a considerably broader range of protein substrates, some of which are essential for normal cell proliferation. Therefore, increasing the selectivity of cyclin-dependent kinase (CDK) inhibitors is critical. Methodology: In this study, we construct a versatile, specific CDK4 pharmacophore model that not only matches well with 8119 of the reported 9349 CDK4/6 inhibitors but also differentiates from the CDK2 pharmacophore. Results & Conclusion: we demonstrate the activity and selectivity determinants of CDK4/6 selective inhibitors based on the CDK4 pharmacophore model. Finally, we propose the future optimization strategy for CDK4/6 selective inhibitors, providing a theoretical basis for further research and development of CDK4/6 selective inhibitors.
Graphical abstract
According to our CDK4 feature model, four decisive factors (capability as a hydrogen bond donor and acceptor, hydrophobicity, electrostatic potential) are highly desirable for potent inhibitory activity and selectivity. At present, most CDK4/6 selective inhibitors have similar skeletons and branches. The structure–activity relationship revealed by the 3D quantitation structure–activity relationships pharmacophore study is illustrated in the following picture. The key hydrogen bond with the hinge region (Val96) is indispensable for activity, although it does not play a major role in selectivity. Along the dotted line, we can design a hetero atom-containing group to form a hydrogen bond interaction with the Lys35CDK4 at the bottom of the binding site. Selectivity is not the effect of a particular residue, but a cumulative effect. A unique hydrogen bonding between the side chain of His95 and the CDK4 inhibitor could improve the selectivity. There is no steric hindrance (Thr102) at the entrance of the binding pocket of CDK4, and the branch A of the scaffold could be designed to be larger such that it is appropriately positively charged and extends to the ‘top’ of the binding site (Asp99) to improve selectivity.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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