Figures & data
Figure 1 Structures and experimental HDAC8 inhibitory activity (pIC50), Pred A (pIC50), and fitness of the known inhibitors (1–32).
Abbreviations: HDAC, histone deacetylase; pIC50, negative logarithm of half maximal inhibitory concentration; Fitness, fitness score; Exp A, experimental activity; Pred A, predicted activity.
![Figure 1 Structures and experimental HDAC8 inhibitory activity (pIC50), Pred A (pIC50), and fitness of the known inhibitors (1–32).](/cms/asset/d0aedaf0-f103-41d8-a731-2d91063a20ed/drmc_a_81388_f0001_b.jpg)
Figure 2 Distribution of activities (pIC50) for the training and test set compounds.
![Figure 2 Distribution of activities (pIC50) for the training and test set compounds.](/cms/asset/4f07074a-ceaf-4aba-bd49-3d368b1a2aa7/drmc_a_81388_f0002_c.jpg)
Table 1 Pharmacophore hypothesis with scoring values
Figure 3 PHASE-generated pharmacophore model of the most active ligand.
![Figure 3 PHASE-generated pharmacophore model of the most active ligand.](/cms/asset/80ec6261-e911-4a96-8698-2cdc619a9c96/drmc_a_81388_f0003_c.jpg)
Table 2 Statistical parameters for the best three pharmacophore hypotheses
Table 3 Structure overlap between coligand and docked orientation and their RMSD values
Table 4 ADME properties of identified hits with recommended range
Figure 5 Fitness graph between the observed and PHASE predicted activity for the training and test set compounds.
![Figure 5 Fitness graph between the observed and PHASE predicted activity for the training and test set compounds.](/cms/asset/17209331-8ca1-48c5-9286-d86d50ea275d/drmc_a_81388_f0005_c.jpg)
Figure 6 Hydrogen bond donor visualization of a three-dimensional QSAR model on the highest active compound (1) and the least active compound (32).
Abbreviation: QSAR, quantitative structure–activity relationship.
![Figure 6 Hydrogen bond donor visualization of a three-dimensional QSAR model on the highest active compound (1) and the least active compound (32).](/cms/asset/70d7cd14-cd66-40e0-bc30-c805fd78f78e/drmc_a_81388_f0006_c.jpg)
Figure 7 Hydrophobic interaction visualization of a three-dimensional QSAR model on compound 1 and compound 32.
Abbreviation: QSAR, quantitative structure–activity relationship.
![Figure 7 Hydrophobic interaction visualization of a three-dimensional QSAR model on compound 1 and compound 32.](/cms/asset/96721cb3-19bc-473d-8ff8-d64ebce0671d/drmc_a_81388_f0007_c.jpg)
Figure 8 Electron withdrawing visual representation of a three-dimensional QSAR model of compound 1 and compound 32.
Abbreviation: QSAR, quantitative structure–activity relationship.
![Figure 8 Electron withdrawing visual representation of a three-dimensional QSAR model of compound 1 and compound 32.](/cms/asset/9c134a7f-7666-43fb-a735-982ad66200f6/drmc_a_81388_f0008_c.jpg)
Figure 9 Important features based on three-dimensional QSAR visualization on compound 1.
![Figure 9 Important features based on three-dimensional QSAR visualization on compound 1.](/cms/asset/b5100d86-d3da-4796-afe1-5646ebada7d0/drmc_a_81388_f0009_c.jpg)
Table 5 Summary of the number of HPB, HBD, HBA, and interactions with Zn
Figure S1 Mapping of ten identified hits with pharmacophore matching and fitness score with compound ID.
![Figure S1 Mapping of ten identified hits with pharmacophore matching and fitness score with compound ID.](/cms/asset/429c2e75-f10b-49b4-980a-28e16cf0f0c8/drmc_a_81388_sf0001_c.jpg)
Figure S2 Experimental activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of known inhibitors.
![Figure S2 Experimental activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of known inhibitors.](/cms/asset/1fc13e6d-2b7d-4a26-b08d-45826b143b2d/drmc_a_81388_sf0002_c.jpg)
Figure S3 Predicted activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of ten potent hits.
![Figure S3 Predicted activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of ten potent hits.](/cms/asset/a7c98fe5-c0a7-406e-8365-1f30b82ff427/drmc_a_81388_sf0003_c.jpg)