The Discovery of a Novel and Selective Inhibitor of PTP1B Over TCPTP: 3D QSAR Pharmacophore Modeling, Virtual Screening, Synthesis, and Biological Evaluation

2014 ◽  
Vol 83 (6) ◽  
pp. 697-709 ◽  
Author(s):  
Ying Ma ◽  
Yuan-Yuan Jin ◽  
Ye-Liu Wang ◽  
Run-Ling Wang ◽  
Xin-Hua Lu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Selective Inhibitor ◽  
Synthesis And Biological Evaluation

scholarly journals Structure-Based Virtual Screening and Biological Evaluation of Peptide Inhibitors for Polo-Box Domain

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 107 ◽  
Author(s):  
Fang Yan ◽  
Guangmei Liu ◽  
Tingting Chen ◽  
Xiaochen Fu ◽  
Miao-Miao Niu
Keyword(s):  
Cell Cycle ◽  
Virtual Screening ◽  
Fold Increase ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Peptide Inhibitors ◽  
Regulatory Proteins ◽  
Competitive Binding Assay ◽  
M Phase ◽  
Cell Cycle Regulatory Proteins

The polo-box domain of polo-like kinase 1 (PLK1-PBD) is proved to have crucial roles in cell proliferation. Designing PLK1-PBD inhibitors is challenging due to their poor cellular penetration. In this study, we applied a virtual screening workflow based on a combination of structure-based pharmacophore modeling with molecular docking screening techniques, so as to discover potent PLK1-PBD peptide inhibitors. The resulting 9 virtual screening peptides showed affinities for PLK1-PBD in a competitive binding assay. In particular, peptide 5 exhibited an approximately 100-fold increase in inhibitory activity (IC50 = 70 nM), as compared with the control poloboxtide. Moreover, cell cycle experiments indicated that peptide 5 effectively inhibited the expression of p-Cdc25C and cell cycle regulatory proteins by affecting the function of PLK1-PBD, thereby inducing mitotic arrest at the G2/M phase. Overall, peptide 5 can serve as a potent lead for further investigation as PLK1-PBD inhibitors.

scholarly journals COMBINATORIAL PHARMACOPHORE MODELING AND ATOM BASED 3D QSAR STUDIES OF BENZOTHIADIAZINES AS HCV-NS5B INHIBITORS

2018 ◽  
Vol 10 (3) ◽  
pp. 43
Author(s):  
Prasanthi Polamreddy ◽  
Vinita Vishwakarma ◽  
Manoj Kumar Mahto
Keyword(s):  
Virtual Screening ◽  
Correlation Coefficient ◽  
Current Model ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Structural Protein ◽  
Pearson's R ◽  
Pearson’S R

Objective: The objective of the current study was to elucidate the 3D pharmacophoric features of benzothiadiazine derivatives that are crucial for inhibiting Hepatitis C virus (HCV) Non-structural protein 5B (NS5B) and quantifying the features by building an atom based 3D quantitative structure-activity relationship (3D QSAR) model.Methods: Generation of QSAR model was carried out using PHASE 3.3.Results: A five-point pharmacophore model with two hydrogen bond acceptors, one negative ionization potential and two aromatic rings (AANRR) was found to be common among a maximum number of benzothiadiazine based NS5B inhibitors. A statistically significant 3D QSAR model was obtained from AANRR.6 which had correlation-coefficient (R2) value of 0.924, cross-validated correlation-coefficient (Q2) of 0.774, high Fisher ratio of 138 and low root mean square standard error (RMSE=0.29). There is another parameter, Pearson’s R, its value emphasizes correlation between predicted and observed activities of the test set. For the current model, Pearson’s R-value is 0.90, hence underlining the good quality of the model. The present study suggests that nitrogen atom of benzothiadiazine sulfamide ring, oxyacetamide group attached to C7 carbon of benzothiadiazine and sulfonamide oxygens are crucial for NS5B inhibitory activity. Prediction of activities of hit drugs generated in earlier research suggests that Aprepitant (Phase predicted activity: 6.9) could be a potential NS5B inhibitor.Conclusion: This 3D QSAR model developed was statistically good and can be used to predict the activities of newly designed NS5B inhibitors and virtual screening as well. Predict the activities of newly designed NS5B inhibitors and virtual screening as well.

scholarly journals Design, synthesis, and biological evaluation of new 6,N2-diaryl-1,3,5-triazine-2,4-diamines as anticancer agents selectively targeting triple negative breast cancer cells

RSC Advances ◽  
2020 ◽  
Vol 10 (43) ◽  
pp. 25517-25528
Author(s):  
Ahmad Junaid ◽  
Felicia Phei Lin Lim ◽  
Edward R. T. Tiekink ◽  
Anton V. Dolzhenko
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Anticancer Agents ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
3D Qsar ◽  
Qsar Model ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation

New highly potent and selective 6,N2-diaryl-1,3,5-triazine-2,4-diamines were designed and prepared using the 3D-QSAR model developed earlier.

Pharmacophore Modeling, Ensemble Docking, Virtual Screening, and Biological Evaluation on Glycogen Synthase Kinase-3β

2014 ◽  
Vol 33 (9) ◽  
pp. 610-626 ◽  
Author(s):  
Gang Fu ◽  
Prasanna Sivaprakasam ◽  
Olivia R. Dale ◽  
Susan P. Manly ◽  
Stephen J. Cutler ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Glycogen Synthase ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Ensemble Docking

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

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Naresh Kandakatla ◽  
Geetha Ramakrishnan
Keyword(s):  
Virtual Screening ◽  
Histone Deacetylases ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Hydrogen Bond Acceptor ◽  
Lipinski’S Rule ◽  
Discovery Studio ◽  
Pharmacophore Generation ◽  
Important Therapeutic Target

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.

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