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    • enfuvirtide The binding pattern of was analysed by flexible

    2019-11-16

    The binding pattern of 1 was analysed by flexible molecular docking. The enfuvirtide inserted into the narrow ATP binding site of CK2 (Fig. 2). As shown the aliphatic chain of 1 was located at the edge of the pocket and established van der Waals interactions with the side chains residues of Ile95, Met163, Val116, Val66 and Ile174. Two hydrogen bonds were observed between the hydroxyl group of 1 and Lys 68, and between the cyano group and Arg47. Other representative interaction was a π-π interaction between the aromatic ring and His160. Based on the binding mode, the presence of different substituents at the phenyl ring to enhance the contact with CK2, modifications in the length side chain to locate the ligand more deeply within the ATP binding site, and the replacement of the cyano moiety by other electron withdrawing groups may increase the inhibitory activity. Thus, the SAR of this class of compounds was investigated by synthesizing structural variations at each of the three sites designated as SAR 1, SAR 2 and SAR 3 (see Scheme 2). In the SAR 1 study, the synthesis was driven by preserving the original functionalities for the SAR 2 and SAR 3 regions in the lead compound, while the SAR 1 position was varied. Various functional groups, such as substituted phenyls, heterocycles and alkyls were introduced in SAR 1. Table 1 shows the structures of SAR 1 compounds and CK2 inhibitory activity. The replacement of chlorine in para position by other halogens such as bromine or fluorine (Table 1, compounds 2–3) led to loss of activity, while the activity was retained when the fluorine was located at meta-position. The effect of withdrawing groups like -CN, -NO2, -CF3, -COOH and -COOMe (Table 1, compounds 6–11) was analysed. The introduction of a nitro group at the para position of the phenyl group (7) showed 4-fold improvement of the CK2 inhibitory activity compared to the lead compound 1. Compound 8 having the nitro group at the meta position was as active as compound 1, and derivative -Ph-4-COOH (10) resulted slightly less active than 1. The rest of the compounds with electron-withdrawing groups (6, 9, 11) did not show good activity, with inhibition percentage lower than 65%. Compound 12 with an unsubstituted phenyl group showed a slightly better activity than compound 1. Regarding the analogues with electron-donating groups (13–15), compound 13 (-Ph-4-OMe) showed slightly better activity than 1, and a loss of activity was observed with additional electron-donating groups (14–15). Substitutions of the phenyl groups with heterocyclic rings were also evaluated (compounds 16–18), the best activity for this series was achieved with the 2-furyl derivative (0.72 ± 0.016) while 3-pyridin and 2-pyridin analogues resulted 1.4 and 1.6-fold less active than 1. The introduction of non-aromatic moieties in the SAR1 position (19–22) resulted in loss of CK2 inhibitory activity. On the basis of the SAR1 findings, a phenyl group or heteroaromatic ring was necessary for the activity, which is supported by the existence of a π-π interaction between the aromatic moiety and His-160 in the Docking model. The different substituents at para- or meta-position modulate the CK2 inhibitory activity depending on the effectiveness of the interactions they establish with the corresponding residues. Thus for instance, the best activity achieved by compound 7 having a 4-NO2 group can be explained on the basis of four hydrogen bond interactions: between the amino group and Leu 45, between the cyano group and Arg 47, between the OH and Lys 68, and between the NO2 group and Lys 158. The aliphatic chain of compound 7 was also located at the edge of the pocket in the same way as compound 1 and established van der Waals interactions with amino acid residues such as Ile95, Ile174, Val 116, Val66 and Phe113 (Fig. 3). Finally, the π-π interaction between the aromatic ring and His 160 was also observed. The interactions with His-160 and Lys-68 are similar to those observed for the potent CK2 inhibitor CX-4945.