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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

Fischer randomization test for 95% confidence level: pharmacophore hypotheses versus total cost.
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fig2: Fischer randomization test for 95% confidence level: pharmacophore hypotheses versus total cost.

Mentions: Fischer randomization test was the third approach to validate the Hypo1 using DS. In this method the experimental activity of the training set compounds was randomly scrambled and generates the random pharmacophore model using the same parameters as used in developing the Hypo1 hypothesis. Confidence level of 95% was set and it created 19 spread sheets, all 19 random spread sheets have high cost values than total cost, and correlation value is less than the Hypo1 (supplementary Table 1). It clearly shows none of the randomly generated pharmacophores has good statistical values than Hypo1. The difference in costs between the HypoGen and Fischer randomizations was shown in Figure 2. All the three validations methods demonstrated that Hypo1 hypothesis has good predictability and can be chosen as the best model.


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

Kandakatla N, Ramakrishnan G - Adv Bioinformatics (2014)

Fischer randomization test for 95% confidence level: pharmacophore hypotheses versus total cost.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Fischer randomization test for 95% confidence level: pharmacophore hypotheses versus total cost.
Mentions: Fischer randomization test was the third approach to validate the Hypo1 using DS. In this method the experimental activity of the training set compounds was randomly scrambled and generates the random pharmacophore model using the same parameters as used in developing the Hypo1 hypothesis. Confidence level of 95% was set and it created 19 spread sheets, all 19 random spread sheets have high cost values than total cost, and correlation value is less than the Hypo1 (supplementary Table 1). It clearly shows none of the randomly generated pharmacophores has good statistical values than Hypo1. The difference in costs between the HypoGen and Fischer randomizations was shown in Figure 2. All the three validations methods demonstrated that Hypo1 hypothesis has good predictability and can be chosen as the best model.

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