3D‐QSAR Study on Apicidin Inhibit Histone Deacetylase

Abstract For Histone Deacetylase (HDAC) Inhibitor, four 3D‐QSAR models for four types of different activities, were constructed. The cross‐validated q 2 value of CoMFA Model 1 is 0.624 and the noncross‐validated r 2 value is 0.939. The cross‐validated q 2 value of Model 2 for training set is 0.652 and the noncross‐validated r 2 value is 0.963. The cross‐validated q 1 value for Model 3 is 0.713, with noncross‐validated r 2 value 0.947. The cross‐validated q 2 value for Model 4 is 0.566 with noncross‐validated r 2 value 0.959. Their predicted abilities were validated by different test sets which did not include in training set. Then the relationship between substituents and activities was analyzed by using these models and the main influence elements in different positions (positions 8 and 14) were found. The polar donor electron group of position 8 could increase the activity of inhibition of HDAC, because it could form chelation with the catalytic Zn. Suitable bulk and positive groups at position 14 are favorable to anti‐HDAC activity. These models could well interpret the relationship between inhibition activity and apicidin structure affording us important information for structure‐based drug design.