Background: Histone deacetylase (HDAC) inhibitors can reactivate gene
expression and inhibit the growth and survival of cancer cells.
Objective: To identify the important pharmacophoric features and correlate 3Dchemical
structure with biological activity using 3D-QSAR and Pharmacophore
Method: The pharmacophore hypotheses were developed using e-pharmacophore
script and phase module. Pharmacophore hypothesis represents the 3D arrangement
of molecular features necessary for activity. A series of 55 compounds with wellassigned
HDAC inhibitory activity were used for 3D-QSAR model development.
Results: Best 3D-QSAR model, which is a five partial least square (PLS) factor
model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated
2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the
selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the
ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried
out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22).
Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222
kcal/mol) and diverse structures.
Conclusion: The structure activity correlation was established using virtual screening, docking,
energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their
validation. The outcomes of these studies could be further employed for the design of novel HDAC
inhibitors for anticancer activity.