There were 35 and 17 drugs within the coaching and test sets related with Clk4, respectively, whilst 31 and 15 drugs had been associated with Dyrk1A, respectively. Compounds with ICs above ten,000 nM12,13 and Dyrk1A 3D QSAR models. The 3D QSAR models with combined eects of hydrogen bond donor, hydrophobic nonpolar, electron withdrawing, and also other functions were visualized in Figure four. Figure 4A and B indicate the cubes generated using the most and least active compounds in training set relating to Clk4. The blue regions indicated favorable capabilities contributing towards the ligand interactions with target enzyme, although the red ones indicated unfavorable features. The eect of the hydrogen bond donor is revealed by the red area around the substitute R1 of comp 52, indicating a hydrogen on the amine group situated on four position on the quinazoline ring is unfavorable for activity.
The results are supported by the evidence that when R1 is changed from an alkyl group to a hydrogen atom, the activity decreases, as is often noticed when comparing comp 1 with comp 14, comp 2 3 with comp 13, comp ten with comp 20, comp five with comp 18, and comp six with comp 9. The comparison amongst the recommended site hydrophobic eects of your most and least active compounds will be observed at position of substituent R3. There is a huge blue region in the ve member ring of your benzodioxol group of comp 1, indicating oxygen or hydrophilic atoms could be favorable at this area. On the contrary, for comp 52, there’s a red area about the methyl group with the 3 methylphenyl group on the R3 substitution, indicating a hydrophobic group attached to the phenyl ring is unfavorable for activity. This observation is constant with trend of activity that when the benzodioxol ring in comp 13 is replaced with much less hydrophilic groups, for instance methylphenyl, methoxybenzene, and chlorophenyl group, the activities decreased drastically.
These final results had been also consistent using the identied pharmacophore function, characterized by a hydrogen bond acceptor situated at the benzodioxol group. The other dierence more hints among the hydro phobic contours relating to comp 1 and comp 52 is the fact that there is a blue location in the 2 position of thiazole ring on R2 substituent of comp 1, indicating a hydrophobic substitute on a meta position could possibly be favorable for activity. The observation is supported by the truth that comp four, using a methyl group around the furan ring, is far more active than comp 20, which will not have a substituent around the furan ring. The oxygen atoms with the benzodioxol ring also contributed towards the electron withdrawing attributes, indicated using a blue area around 1,three dioxol group of comp 1. The combinational eects of hydrogen bond donor, hydro phobic nonpolar, electron withdrawing, as well as other characteristics concerning Dyrk1A are visualized in Figure 4C and D.