Abstract
Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.
Highlights
Ligand and structure-based computer-aided drug design strategies includes several computational approaches that have been repeatedly applied to design and discover the new molecules
Pharmacophoric model was developed by Phase module and e-pharmacophore mapping on compound 1
The pharmacophoric models were characterized by a set of points in 3D space, which correspond to a variety of chemical features which may assist non-covalent binding between the ligand molecule and its corresponding target receptor
Summary
Ligand and structure-based computer-aided drug design strategies includes several computational approaches that have been repeatedly applied to design and discover the new molecules. 1) and other HDACi hamper different classes of histone deacetylases (HDACs) by interacting with the active pocket site of HDAC proteins leading to interfere with different tumor mediators. All these HDACi have four essential structural elements such as a surface recognition cap group, a connecting unit, a linker moiety and a zinc-binding domain (ZBD). The key intention of the present study was to apply the structure and ligand-based tactics to recognize the importance of heterocyclic connecting unit at SAHA analogs. This study consists of numerous consecutive steps such as preparation of data set, the establishment of structure-activity relationship by 3D QSAR approach, molecular docking of ligands in the active site of a protein molecule, e-pharmacophore mapping and establishment of a correlation between structure and biological activity
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