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Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer
Gul Bushra Khan1, Muhammad Qasim1, Azhar Rasul2
1Department of Bioinformatics and Biotechnology, Faculty of Life Sciences, Government College University, Faisalabad 38000, Pakistan.
Researchers identified potential lung cancer drugs by virtually screening 17,000 natural compounds targeting the 6-phosphogluconate dehydrogenase (6-PGD) enzyme. Three lignan compounds, secoisolariciresinol, syringaresinol, and cleomiscosin A, showed promising anticancer activity and stability, warranting further investigation.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Targeting enzymes in the pentose phosphate pathway (PPP) is a key strategy for cancer treatment.
- 6-Phosphogluconate dehydrogenase (6-PGD) is overexpressed in many cancers and is a potential drug target.
- Identifying novel inhibitors of 6-PGD is crucial for developing new anticancer therapies.
Purpose of the Study:
- To discover novel inhibitors of 6-PGD using virtual screening and structure-based drug design.
- To evaluate the anticancer potential of identified compounds through in silico and in vitro assays.
- To identify lead compounds for lung cancer therapy targeting 6-PGD.
Main Methods:
- Virtual screening of 17,000 natural compounds against the 6-PGD binding site using molecular operating environment (MOE).
- In silico ADMET assessment, molecular dynamics (MD) simulations, and cytotoxicity prediction (CLC-Pred).
- In vitro enzymatic assays, MTT assays, and flow cytometry analysis using A549 lung cancer cells.
Main Results:
- 115 potential 6-PGD inhibitors were identified, with 5 showing favorable pharmacokinetic profiles.
- Secoisolariciresinol, syringaresinol, and cleomiscosin A demonstrated stable binding and anticancer activity.
- Syringaresinol (IC50 = 36.9 μg/mL) and cleomiscosin A (IC50 = 133 μg/mL) induced apoptosis in A549 cells.
Conclusions:
- Secoisolariciresinol, syringaresinol, and cleomiscosin A are promising lead candidates for lung cancer treatment via 6-PGD inhibition.
- The identified lignans exhibit dose-dependent apoptosis induction in lung cancer cells.
- Further in vivo studies are recommended to confirm the efficacy of these compounds.
