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Ligand Based Pharmacophore Modeling and Virtual Screening Studies to Design Novel HDAC2 Inhibitors.

Kandakatla N, Ramakrishnan G - Adv Bioinformatics (2014)

Bottom Line: A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio.This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski's rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX).Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Sathyabama University, Jeppiaar Nagar, Chennai 600119, India.

ABSTRACT
Histone deacetylases 2 (HDAC2), Class I histone deacetylase (HDAC) family, emerged as an important therapeutic target for the treatment of various cancers. A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio. The best HypoGen model consists of four pharmacophore features namely, one hydrogen bond acceptor (HBA), and one hydrogen donor (HBD), one hydrophobic (HYP) and one aromatic centres, (RA). This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski's rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX). Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of virtual screening process implemented in the identification of HDAC2 inhibitors.
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fig3: Schematic representation of virtual screening process implemented in the identification of HDAC2 inhibitors.

Mentions: The best pharmacophore model Hypo1 was used as a 3D query to search the NCI (265242) and Maybridge (58723) databases using flexible search option in DS. A total of 6130 compounds from NCI and 1379 from Maybridge were mapped using the features of Hypo1. A total of 1198 and 440 compounds from NCI and Maybridge showed HypoGen estimated value of less than 1 μM and were considered for further studies and these compounds were screened for Lipinski's rule of 5. A total of 625 (382 NCI, 243 Maybridge) compounds obeyed the rule and were subjected to molecular docking studies. The flowchart in Figure 3 was a schematic representation of virtual screening process.


Ligand Based Pharmacophore Modeling and Virtual Screening Studies to Design Novel HDAC2 Inhibitors.

Kandakatla N, Ramakrishnan G - Adv Bioinformatics (2014)

Schematic representation of virtual screening process implemented in the identification of HDAC2 inhibitors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265523&req=5

fig3: Schematic representation of virtual screening process implemented in the identification of HDAC2 inhibitors.
Mentions: The best pharmacophore model Hypo1 was used as a 3D query to search the NCI (265242) and Maybridge (58723) databases using flexible search option in DS. A total of 6130 compounds from NCI and 1379 from Maybridge were mapped using the features of Hypo1. A total of 1198 and 440 compounds from NCI and Maybridge showed HypoGen estimated value of less than 1 μM and were considered for further studies and these compounds were screened for Lipinski's rule of 5. A total of 625 (382 NCI, 243 Maybridge) compounds obeyed the rule and were subjected to molecular docking studies. The flowchart in Figure 3 was a schematic representation of virtual screening process.

Bottom Line: A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio.This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski's rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX).Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Sathyabama University, Jeppiaar Nagar, Chennai 600119, India.

ABSTRACT
Histone deacetylases 2 (HDAC2), Class I histone deacetylase (HDAC) family, emerged as an important therapeutic target for the treatment of various cancers. A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio. The best HypoGen model consists of four pharmacophore features namely, one hydrogen bond acceptor (HBA), and one hydrogen donor (HBD), one hydrophobic (HYP) and one aromatic centres, (RA). This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski's rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX). Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors.

No MeSH data available.


Related in: MedlinePlus