We recently reported novel purine-based CK2α inhibitors using the solvent ordering-based method as virtual screening. Among these, the X-ray crystal structure of a complex with CK2α was determined. The results showed that the crystalline water molecules observed in many previously reported complex structures of CK2α and its inhibitors had been eliminated. We then proposed a structure-based drug design. Since the removal of water molecules would be detrimental to inhibitor binding, new groups of compounds were designed by changing the position of the carboxy group located at the point where a water molecule would be present so as not to eliminate it. Compounds with (E)-2-carboxyethenyl and 3-carboxyphenyl substituted at the 2-position on the purine scaffold showed much higher inhibitory potency than 4-carboxyphenyl derivatives. Furthermore, in the presence of a 4-fluorophenyl group at the 9-position on the purine scaffold, the inhibitory activity of the 3-carboxyphenyl derivative against CK2α was 0.18 μM, a 167-fold improvement compared to the 4-carboxyphenyl derivative. The strategy of leaving crystalline water can significantly increase inhibitory activity.
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