Structure-Based Virtual Screening of Nigella sativa Compounds as Potential Anti-Lung Cancer Agents Targeting PI3Kα
Abstract
Background: Lung cancer (LC) is one of the deadliest tumors. Hyperactivation of phosphatidylinositol 3-kinase (PI3K) has been linked to cancer etiology.
Methods: This study computationally screens the Nigella sativa compounds and their interactions with PI3Kα to identify potential therapeutic agents for LC. Copanlisib was chosen as the positive control for virtual screening. The LOTUS database was used to produce a library of 132 compounds that represent bioactive components of N. sativa. Molecular properties and molecular descriptors of N. sativa compounds were obtained from the LOTUS database.
Results: Compounds were ranked based on their binding energy to PI3Kα and interactions with key residues in the PI3Kα binding pocket. The screening identified five compounds as top hits: LTS0117717, LTS0169227, LTS0183019, LTS0241372, and LTS0249588, which had stronger binding energy than the control Copanlisib. LTS0117717, LTS0169227, LTS0183019, LTS0241372, and LTS0249588 had binding energies of -9.8, -9.6, -9.5, -9.1, and -9.0 kcal/mol, respectively, while the Copanlisib (control) had a binding energy of -8.6 kcal/mol. These compounds interacted with active site residues of PI3Kα. In addition, these compounds have good druglike properties.
Conclusion: The compounds LTS0117717, LTS0169227, LTS0183019, LTS0241372, and LTS0249588 can be used as PI3Kα inhibitors to treat the LC. However, further experimental studies are warranted to validate these compounds as PI3Kα inhibitors.
Keywords: Lung cancer; PI3Kα; Nigella sativa; Drug likeness
Full Text:
PDFReferences
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. Journal of Thoracic Oncology, (2011); 6(2): 244-285.
Diederich S, Wormanns D, Heindel W. Lung cancer screening with low-dose CT. European Journal of Radiology, (2003); 45(1): 2-7.
Paech DC, Weston AR, Pavlakis N, Gill A, Rajan N, et al. A systematic review of the interobserver variability for histology in the differentiation between squamous and nonsquamous non-small cell lung cancer. Journal of Thoracic Oncology, (2011); 6(1): 55-63.
Sakre N, Wildey G, Behtaj M, Kresak A, Yang M, et al. RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR. Oncotarget, (2017); 8(4): 5992-6002.
Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nature Reviews Disease Primers, (2021); 7(1): 3.
Das S, Roy S, Rahaman SB, Akbar S, Ahmed B, et al. Structure-Activity Relationship Insight of Naturally Occurring Bioactive Molecules and Their Derivatives Against Non-Small Cell Lung Cancer: A Comprehensive Review. Current Medicinal Chemistry, (2022); 29(39): 6030-6062.
Tan AC. Targeting the PI3K/Akt/mTOR pathway in non-small cell lung cancer (NSCLC). Thoracic Cancer, (2020); 11(3): 511-518.
Haider K, Ahmad K, Najmi AK, Das S, Joseph A, Shahar Yar M. Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kalpha inhibitors. Archiv der Pharmazie, (2022); 355(10): e2200146.
Cheng H, Orr STM, Bailey S, Brooun A, Chen P, et al. Structure-Based Drug Design and Synthesis of PI3Kalpha-Selective Inhibitor (PF-06843195). Journal of Medicinal Chemistry, (2021); 64(1): 644-661.
Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorganic & Medicinal Chemistry Letters, (2013); 23(13): 3741-3748.
Niazi SK, Mariam Z. Computer-Aided Drug Design and Drug Discovery: A Prospective Analysis. Pharmaceuticals (Basel), (2023); 17(1): 22.
Sadybekov AV, Katritch V. Computational approaches streamlining drug discovery. Nature, (2023); 616(7958): 673-685.
Li Q, Shah S. Structure-Based Virtual Screening. Methods in Molecular Biology, (2017); 1558: 111-124.
Kratzer TB, Bandi P, Freedman ND, Smith RA, Travis WD, et al. Lung cancer statistics, 2023. Cancer, (2024); 130(8): 1330-1348.
Luo G, Zhang Y, Etxeberria J, Arnold M, Cai X, et al. Projections of Lung Cancer Incidence by 2035 in 40 Countries Worldwide: Population-Based Study. JMIR Public Health and Surveillance, (2023); 9: e43651.
Xue X, Ye G, Zhang L, Zhu X, Liu Q, et al. PI3Kalpha inhibitor GNE-493 triggers antitumor immunity in murine lung cancer by inducing immunogenic cell death and activating T cells. International Immunopharmacology, (2024); 130: 111747.
Nazam N, Lone MI, Hamid A, Qadah T, Banjar A, et al. Dimethoate Induces DNA Damage and Mitochondrial Dysfunction Triggering Apoptosis in Rat Bone-Marrow and Peripheral Blood Cells. Toxics, (2020); 8(4): 80.
Sait KHW, Mashraqi M, Khogeer AA, Alzahrani O, Anfinan NM, et al. Molecular docking analysis of HER-2 inhibitor from the ZINC database as anticancer agents. Bioinformation, (2020); 16(11): 882-887.
Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Annals of Oncology, (2017); 28(9): 2169-2178.
Alqahtani LS, Alkathiri AS, Alzahrani A, Alghamdi RM, Alamri WA, et al. Structure-Based Virtual Screening of Antiviral Compounds Targeting the Norovirus RdRp Protein. Advancements in Life Sciences, (2024); 11(2): 488-492.
Kamal MA, Baeissa HM, Hakeem IJ, Alazragi RS, SHazzazi M, et al. Insights from the molecular docking analysis of EGFR antagonists. Bioinformation, (2023); 19(3): 260-265.
Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iranian Journal of Basic Medical Sciences, (2014); 17(12): 929-938.
Abbas M, Gururani MA, Ali A, Bajwa S, Hassan R, et al. Antimicrobial Properties and Therapeutic Potential of Bioactive Compounds in Nigella sativa: A Review. Molecules, (2024); 29(20): 4914.
Shafiq H, Ahmad A, Masud T, Kaleem M. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa. Iranian Journal of Basic Medical Sciences, (2014); 17(12): 967-979.
DOI: http://dx.doi.org/10.62940/als.v12i4.3761
Refbacks
- There are currently no refbacks.