Advanced search
Publication Cover
Research and Reports in Medicinal Chemistry Volume 5, 2015 - Issue
Journal homepage
79
Views
1
CrossRef citations to date
0
Altmetric
Original Research

Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study

Tanusree Debnath1 Department of Chemistry, MBB College, Agartala, Tripura
,
Swapan Majumdar2 Department of Chemistry, Tripura University, Suryamanninagar, Agartala, Tripura
,
Arunasree M Kalle3 University of Hyderabad Gachibowli, Hyderabad
,
Vema Aparna4 Sree Chaitanya Institute of Pharmaceutical Sciences, Karimnagar, India
&
Sudhan Debnath1 Department of Chemistry, MBB College, Agartala, TripuraCorrespondence[email protected]
Pages 21-39 | Published online: 25 Jun 2015

Figures & data

Figure 1 Structures and experimental HDAC8 inhibitory activity (pIC50), Pred A (pIC50), and fitness of the known inhibitors (1–32).

Note: *Test set.
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).

Figure 2 Distribution of activities (pIC50) for the training and test set compounds.

Abbreviation: pIC50, negative logarithm of half maximal inhibitory concentration.
Figure 2 Distribution of activities (pIC50) for the training and test set compounds.

Table 1 Pharmacophore hypothesis with scoring values

Figure 3 PHASE-generated pharmacophore model of the most active ligand.

Notes: AADDRR, AADHRR, and AADDHR illustrating the hydrogen bond acceptor (A; pink), hydrogen bond donor (D; blue), hydrophobic group (H; green), and aromatic ring (R; orange) features.
Figure 3 PHASE-generated pharmacophore model of the most active ligand.

Table 2 Statistical parameters for the best three pharmacophore hypotheses

Table 3 Structure overlap between coligand and docked orientation and their RMSD values

Figure 4 Workflow for the virtual screening protocol.

Abbreviation: XPGS, XP Glide score.
Figure 4 Workflow for the virtual screening protocol.

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.

Notes: (A) Training set; (B) test set. *A model with four partial least squares factors was considered as the best statistical model.
Figure 5 Fitness graph between the observed and PHASE predicted activity for the training and test set compounds.

Figure 6 Hydrogen bond donor visualization of a three-dimensional QSAR model on the highest active compound (1) and the least active compound (32).

Notes: (A) Active compound 1; (B) least active compound 32. Blue cubes indicate favorable regions, while orange cubes indicate unfavorable regions.
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).

Figure 7 Hydrophobic interaction visualization of a three-dimensional QSAR model on compound 1 and compound 32.

Notes: (A) Compound 1; (B) compound 32. Green cubes indicate favorable regions, while purple cubes indicate unfavorable regions for activity.
Abbreviation: QSAR, quantitative structure–activity relationship.
Figure 7 Hydrophobic interaction visualization of a three-dimensional QSAR model on compound 1 and compound 32.

Figure 8 Electron withdrawing visual representation of a three-dimensional QSAR model of compound 1 and compound 32.

Notes: (A) Compound 1; (B) compound 32. Blue cubes indicate favorable regions, while orange cubes indicate unfavorable regions for activity.
Abbreviation: QSAR, quantitative structure–activity relationship.
Figure 8 Electron withdrawing visual representation of a three-dimensional QSAR model of compound 1 and compound 32.

Figure 9 Important features based on three-dimensional QSAR visualization on compound 1.

Abbreviation: QSAR, quantitative structure–activity relationship.
Figure 9 Important features based on three-dimensional QSAR visualization on compound 1.

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.

Abbreviation: Fitness, fitness score.
Figure S1 Mapping of ten identified hits with pharmacophore matching and fitness score with compound ID.

Figure S2 Experimental activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of known inhibitors.

Abbreviations: pIC50, negative logarithm of half maximal inhibitory concentration; XPGS, XP Glide score; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor.
Figure S2 Experimental activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of known inhibitors.

Figure S3 Predicted activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of ten potent hits.

Abbreviations: pIC50, negative logarithm of half maximal inhibitory concentration; XPGS, XP Glide score; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor; Fitness, fitness score.
Figure S3 Predicted activity (pIC50), XPGS, type of interaction (HBD and HBA), and Zn (interaction distance) of ten potent hits.

Figure S4 Superposition of reported hits on the coligand of the X-ray ligand–enzyme complex of 1T64 and RMSD values.

Note: Coligand is shown in green.
Abbreviation: RMSD, root-mean-square deviation.
Figure S4 Superposition of reported hits on the coligand of the X-ray ligand–enzyme complex of 1T64 and RMSD values.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.