Background: Overexpression of Histone deacetylase 1 (HDAC1) is responsible for carcinogenesis
by promoting epigenetic silence of tumour suppressor genes. Thus, HDAC1 inhibitors have
emerged as the potential therapeutic leads against multiple human cancers, as they can block the activity
of particular HDACs, renovate the expression of several tumour suppressor genes and bring about
cell differentiation, cell cycle arrest and apoptosis.
Methods: The present research work comprises atom-based 3D-QSAR, docking, molecular dynamic
simulations and DFT (density functional theory) studies on a diverse series of hydroxamic acid derivatives
as selective HDAC1 inhibitors. Two pharmacophoric models were generated and validated by
calculating the enrichment factors with the help of the decoy set. The Four different 3D-QSAR models
i.e., PLS (partial least square) model, MLR (multiple linear regression) model, Field-based model and
GFA (Genetic function approximation) model were developed using ‘PHASE’ v3.4 (Schrödinger) and
Discovery Studio (DS) 4.1 software and validated using different statistical parameters like internal
and external validation.
Results and Discussion: The results showed that the best PLS model has R2=0.991 and Q2=0.787, the
best MLR model has R2= 0.993 and Q2= 0.893, the best Field-based model has R2= 0.974 and Q2=
0.782 and the best GFA model has R2= 0.868 and Q2= 0.782. Cross-validated coefficients, (rcv
0.967, 0.926, 0.966 and 0.829 was found for PLS model, MLR, Field based and GFA model, respectively,
indicated the satisfactory correlativity and prediction. The docking studies were accomplished
to find out the conformations of the molecules and their essential binding interactions with the target
protein. The trustworthiness of the docking results was further confirmed by molecular dynamics (MD)
simulations studies. Density Functional Theory (DFT) study was performed which promptly optimizes
the geometry, stability and reactivity of the molecule during receptor-ligand interaction.
Conclusion: Thus, the present research work provides spatial fingerprints which would be beneficial
for the development of potent HDAC1 inhibitors.