Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer
Targeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. O...
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MDPI AG
2022-12-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/1/34 |
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| author | Gul Bushra Khan Muhammad Qasim Azhar Rasul Usman Ali Ashfaq Abdullah M. Alnuqaydan |
| author_facet | Gul Bushra Khan Muhammad Qasim Azhar Rasul Usman Ali Ashfaq Abdullah M. Alnuqaydan |
| author_sort | Gul Bushra Khan |
| collection | DOAJ |
| description | Targeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. Overexpression of 6-PGD has been reported in multiple cancers and is recognized as a potential anticancer drug target. The current study is focused on the utilization of indispensable virtual screening tools for structure-based drug discovery. During the study, 17,000 natural compounds were screened against the 3-phosphoglycerate (3-PG) binding site of 6-PGD through a molecular operating environment (MOE), which revealed 115 inhibitors with higher selectivity and binding affinity. Out of the 115 best-fit compounds within the 6-PGD binding cavity, 15 compounds were selected and optimized through stringent in silico ADMET assessment models that justified the desirable pharmacokinetic, pharmacodynamic and physicochemical profiles of 5 ligands. Further protein–ligand stability assessment through molecular dynamics (MD) simulation illustrated three potential hits, secoisolariciresinol, syringaresinol and cleomiscosin A, with stable confirmation. Moreover, 6-PGD inhibitor validation was performed by an in vitro enzymatic assay using human erythrocytes purified 6-PGD protein and A549 cell lysate protein. The results of the in vitro assays supported the in silico findings. In order to gain insight into the anticancer activity of the aforementioned compounds, they were subjected to CLC-Pred, an in silico cytotoxicity browsing tool, which proved their anticancer activity against several cancer cell lines at Pa > 0.5. Additionally, a confirmation for in silico cytotoxicity was made by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for commercially available hits syringaresinol and cleomiscosin A against lung cancer (A549) cells. The results demonstrated that syringaresinol has an IC<sub>50</sub> value of 36.9 μg/mL, while cleomiscosin A has an IC<sub>50</sub> value of 133 μg/mL. After MTT, flow cytometry analysis confirmed that compounds induced apoptosis in A549 cells in a dose-dependent manner. This study suggested that the respective lignan compounds can serve as lead candidates for lung cancer therapy via 6-PGD inhibition. Furthermore, in vivo experiments need to be conducted to confirm their efficacy. |
| first_indexed | 2024-03-09T11:43:22Z |
| format | Article |
| id | doaj.art-42b4588879204f3a872da0656a957124 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-09T11:43:22Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
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| spelling | doaj.art-42b4588879204f3a872da0656a9571242023-11-30T23:27:55ZengMDPI AGMetabolites2218-19892022-12-011313410.3390/metabo13010034Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung CancerGul Bushra Khan0Muhammad Qasim1Azhar Rasul2Usman Ali Ashfaq3Abdullah M. Alnuqaydan4Department of Bioinformatics and Biotechnology, Faculty of Life Sciences, Government College University, Faisalabad 38000, PakistanDepartment of Bioinformatics and Biotechnology, Faculty of Life Sciences, Government College University, Faisalabad 38000, PakistanDepartment of Zoology, Faculty of Life Sciences, Government College University, Faisalabad 38000, PakistanDepartment of Bioinformatics and Biotechnology, Faculty of Life Sciences, Government College University, Faisalabad 38000, PakistanDepartment of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi ArabiaTargeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. Overexpression of 6-PGD has been reported in multiple cancers and is recognized as a potential anticancer drug target. The current study is focused on the utilization of indispensable virtual screening tools for structure-based drug discovery. During the study, 17,000 natural compounds were screened against the 3-phosphoglycerate (3-PG) binding site of 6-PGD through a molecular operating environment (MOE), which revealed 115 inhibitors with higher selectivity and binding affinity. Out of the 115 best-fit compounds within the 6-PGD binding cavity, 15 compounds were selected and optimized through stringent in silico ADMET assessment models that justified the desirable pharmacokinetic, pharmacodynamic and physicochemical profiles of 5 ligands. Further protein–ligand stability assessment through molecular dynamics (MD) simulation illustrated three potential hits, secoisolariciresinol, syringaresinol and cleomiscosin A, with stable confirmation. Moreover, 6-PGD inhibitor validation was performed by an in vitro enzymatic assay using human erythrocytes purified 6-PGD protein and A549 cell lysate protein. The results of the in vitro assays supported the in silico findings. In order to gain insight into the anticancer activity of the aforementioned compounds, they were subjected to CLC-Pred, an in silico cytotoxicity browsing tool, which proved their anticancer activity against several cancer cell lines at Pa > 0.5. Additionally, a confirmation for in silico cytotoxicity was made by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for commercially available hits syringaresinol and cleomiscosin A against lung cancer (A549) cells. The results demonstrated that syringaresinol has an IC<sub>50</sub> value of 36.9 μg/mL, while cleomiscosin A has an IC<sub>50</sub> value of 133 μg/mL. After MTT, flow cytometry analysis confirmed that compounds induced apoptosis in A549 cells in a dose-dependent manner. This study suggested that the respective lignan compounds can serve as lead candidates for lung cancer therapy via 6-PGD inhibition. Furthermore, in vivo experiments need to be conducted to confirm their efficacy.https://www.mdpi.com/2218-1989/13/1/34in silicodocking6-PGDnatural inhibitorsenzymatic assayMD simulation |
| spellingShingle | Gul Bushra Khan Muhammad Qasim Azhar Rasul Usman Ali Ashfaq Abdullah M. Alnuqaydan Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer Metabolites in silico docking 6-PGD natural inhibitors enzymatic assay MD simulation |
| title | Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer |
| title_full | Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer |
| title_fullStr | Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer |
| title_full_unstemmed | Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer |
| title_short | Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer |
| title_sort | identification of lignan compounds as new 6 phosphogluconate dehydrogenase inhibitors for lung cancer |
| topic | in silico docking 6-PGD natural inhibitors enzymatic assay MD simulation |
| url | https://www.mdpi.com/2218-1989/13/1/34 |
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