A theoretical study of the structure and protonation of Palbociclib (PD 0332991)

• Palbociclib (CDK4/6 inhibitor) has been promoted for breast cancer treatment.
• The predominant tautomer of Palbociclib is an imino and not an amino form as usually represented.
• The structure of Palbociclib embedded in a protein is a cation.
• The site of protonation of Palbociclib has been determined.

The geometry, protonation and chemical shifts of the important new drug, Palbociclib (8-cyclopentyl-6-ethanoyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), have been studied theoretically. The conclusion is that in the active site of its target enzyme, Palbociclib exists as a cation protonated on the nitrogen atom of the pyridine ring. The tautomerism of the neutral form in solution has also been determined indicating that it is a mixture of two imino tautomers in fast equilibrium.

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