Abstract
In view of the emerging clinical indications for Phosphodiesterase 9 inhibitors e.g. treatment of Alzheimer, diabetes, cancer, and the limited number of its selective inhibitors which possess a single chemical scaffolds, a structure-based approach was undertaken to mine the ZINC database by virtual screening to identify novel PDE9 inhibitors. The database, which was never reported to have been used before for discovery of PDE9 inhibitors, was screened against the ligand binding pocket of the PDE9 complex (PDB:4GH6) using molecular docking programs, MOE and AutoDock Vina in PyRx. Three different scoring functions were used to evaluate the docking poses and scores of the compounds, and the compounds were selected through consensus selection, thus reducing the margin of error in docking. The highest scoring compounds were then selected and purchased for in vitro testing as PDE9 inhibitors and cancer growth inhibitory agents. This led to the discovery of three previously unreported potent PDE 9 inhibitory compounds with two unique chemical scaffolds. Consistent with the role of PDE9 in cancer cell growth, the compounds also inhibited the growth of breast tumor cell lines, MCF-7 and MDA-468 at concentrations comparable to those that inhibited PDE9.
Keywords: Phosphodiesterase 9 inhibitors, virtual screening, ZINC database.
Medicinal Chemistry
Title:Mining ZINC Database to Discover Potential Phosphodiesterase 9 Inhibitors Using Structure-Based Drug Design Approach
Volume: 12 Issue: 5
Author(s): Engi A. Hassaan, Sara C. Sigler, Tamer M. Ibrahim, Kevin J. Lee, Lauren K. Cichon, Bernard D. Gary, Joshua C. Canzoneri, Gary A. Piazza and Ashraf H.Abadi
Affiliation:
Keywords: Phosphodiesterase 9 inhibitors, virtual screening, ZINC database.
Abstract: In view of the emerging clinical indications for Phosphodiesterase 9 inhibitors e.g. treatment of Alzheimer, diabetes, cancer, and the limited number of its selective inhibitors which possess a single chemical scaffolds, a structure-based approach was undertaken to mine the ZINC database by virtual screening to identify novel PDE9 inhibitors. The database, which was never reported to have been used before for discovery of PDE9 inhibitors, was screened against the ligand binding pocket of the PDE9 complex (PDB:4GH6) using molecular docking programs, MOE and AutoDock Vina in PyRx. Three different scoring functions were used to evaluate the docking poses and scores of the compounds, and the compounds were selected through consensus selection, thus reducing the margin of error in docking. The highest scoring compounds were then selected and purchased for in vitro testing as PDE9 inhibitors and cancer growth inhibitory agents. This led to the discovery of three previously unreported potent PDE 9 inhibitory compounds with two unique chemical scaffolds. Consistent with the role of PDE9 in cancer cell growth, the compounds also inhibited the growth of breast tumor cell lines, MCF-7 and MDA-468 at concentrations comparable to those that inhibited PDE9.
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Cite this article as:
A. Hassaan Engi, C. Sigler Sara, M. Ibrahim Tamer, J. Lee Kevin, K. Cichon Lauren, D. Gary Bernard, C. Canzoneri Joshua, A. Piazza Gary and H.Abadi Ashraf, Mining ZINC Database to Discover Potential Phosphodiesterase 9 Inhibitors Using Structure-Based Drug Design Approach, Medicinal Chemistry 2016; 12 (5) . https://dx.doi.org/10.2174/1573406412666151204002836
DOI https://dx.doi.org/10.2174/1573406412666151204002836 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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