Journal of PhytoPharmaceutical and Advanced Chemistry
Short Name: JPPAC• ISSN: 3139-9266• Peer-Reviewed Open Access
Computational Assessment of Secondary Metabolites as Potential Inhibitors of Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2)
Abstract
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme involved in one-carbon metabolism and is highly upregulated in rapidly proliferating cancer cells, making it a promising therapeutic target. In this study, five structurally diverse secondary metabolites—catechin, kaempferol, rutin, licochalcone A, and carolacton—were computationally evaluated as potential MTHFD2 inhibitors using an integrated molecular docking and ADMET approach. Docking simulations were performed using PyRx with AutoDock against the crystal structure of MTHFD2 (PDB ID: 6KG2), and interaction profiles were analyzed using Discovery Studio Visualizer. Catechin and kaempferol demonstrated the strongest binding affinities (−7.1 kcal/mol), exceeding that of the native ligand (−5.9 kcal/mol), and formed stable hydrogen bonding and hydrophobic interactions with key catalytic residues including TYR84, ILE276, and THR316. Licochalcone A and carolacton showed moderate binding potential, whereas rutin exhibited weaker affinity, likely due to steric hindrance from its glycosidic moiety. Comprehensive ADMET profiling using SwissADME and ADMETlab 3.0 indicated that catechin and kaempferol possess favorable physicochemical properties, good drug-likeness, and comparatively safer metabolic and toxicity profiles. Environmental toxicity predictions further suggested acceptable ecological safety across the evaluated compounds. Overall, catechin and kaempferol emerge as promising natural scaffolds for MTHFD2 inhibition. Further in vitro and in vivo studies are required to validate their therapeutic potential and translational applicability.
Research Keywords & Fields
Export Citation
Generate ready-to-use citations in standard scientific formats
Cited References
- 01.
1. Cronauer M V., Hittmair A, Eder IE, Hobisch A, Culig Z, Ramoner R, et al. Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate. Prostate. 1997;31(4):223–33.
- 02.
2. Shuvalov O, Petukhov A, Daks A, Fedorova O, Vasileva E, Barlev NA. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Vol. 8, Oncotarget. 2017. p. 23955–77.
- 03.
3. Mo J, Gao Z, Zheng L, Yan M, Xue M, Xu J, et al. Targeting mitochondrial one-carbon enzyme MTHFD2 together with pemetrexed confers therapeutic advantages in lung adenocarcinoma. Cell Death Discov. 2022;8(1):307.
- 04.
4. Nieto MA. Epithelial plasticity: A common theme in embryonic and cancer cells. Vol. 342, Science. 2013; 342(6159):1234850.
- 05.
5. Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014;5:3128.
- 06.
6. Zhu Z, Leung GKK. More Than a Metabolic Enzyme: MTHFD2 as a Novel Target for Anticancer Therapy? Vol. 10, Frontiers in Oncology. 2020;10:658.
- 07.
7. Al-Khayri JM, Rashmi R, Toppo V, Chole PB, Banadka A, Sudheer WN, et al. Plant Secondary Metabolites: The Weapons for Biotic Stress Management. Vol. 13, Metabolites. 2023;13(6):716.
- 08.
8. Alshammari SO. Identification and Absorption–Distribution–Metabolism–Excretion–Toxicity Prediction of Potential MTHFD2 Enzyme Inhibitors from Urtica dioica Ethanolic Leaf Extract. Processes. 2024;12(6):1177.
- 09.
9. Tian Y, Jia X, Wang Q, Lu T, Deng G, Tian M, et al. Antioxidant, Antibacterial, Enzyme Inhibitory, and Anticancer Activities and Chemical Composition of Alpinia galanga Flower Essential Oil. Pharmaceuticals. 2022;15(9):1069.
- 10.
10. GÜÇLÜ G, ERGÜL M, UÇAR E, ERUYGUR N, ATAŞ M, AKPULAT HA. Anticancer, Antioxidant, Antimicrobial and Enzyme Inhibitory Activities of Inula aucheriana. Kahramanmaraş Sütçü İmam Üniversitesi Tarım ve Doğa Derg. 2022;25(5):946–54.
- 11.
11. Jan R, Khan M, Asaf S, Lubna, Asif S, Kim KM. Bioactivity and Therapeutic Potential of Kaempferol and Quercetin: New Insights for Plant and Human Health. Plants. 2022;11(19):2623.
- 12.
12. Baranwal A, Aggarwal P, Rai A, Kumar N. Pharmacological Actions and Underlying Mechanisms of Catechin: A Review. Mini-Reviews Med Chem. 2021;22(5):821–33.
- 13.
13. Al-Dhabi NA, Arasu MV, Park CH, Park SU. An up-to-date review of rutin and its biological and pharmacological activities. Vol. 14, EXCLI Journal. 2015;14:59–63.
- 14.
14. Liu M, Du Y, Gao D. Licochalcone A: a review of its pharmacology activities and molecular mechanisms. Front Pharmacol. 2024;15:1453426.
- 15.
15. Hedges MR, Di Carlo CM, Wuest WM. Combatting resistance: natural products as tools to drive the discovery of untapped antibiotic targets. Vol. 61, Chemical Communications. 2025; 61:14039-14058.
- 16.
16. Kharkar P. Two-Dimensional (2D) In Silico Models for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) in Drug Discovery. Curr Top Med Chem. 2010;10(1):116–26.
- 17.
17. Kawai J, Toki T, Ota M, Inoue H, Takata Y, Asahi T, et al. Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity. J Med Chem. 2019; 62(22):10204-10220.
- 18.
18. Ju HQ, Lu YX, Chen DL, Zuo ZX, Liu ZX, Wu QN, et al. Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications. J Natl Cancer Inst. 2019;111(6):584–96.
- 19.
19. Alhawarri MB. Schweinfurthiamide as a Promising Anticancer Agent: Molecular Docking, Dynamics, and ADMET Insights Targeting MTHFD2. J Pharm Innov. 2025;20(5):189.
- 20.
20. Vawhal PK, Jadhav SB, Kaushik S, Panigrahi KC, Nayak C, Urmee H, et al. Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay. Molecules. 2023;28(3):1004.
- 21.
21. Begh MZA, Zehravi M, Reza F, Sweilam SH, Shanmugarajan TS, Arjun UVNV, et al. Therapeutic potential of phytocompounds in rheumatoid arthritis: Molecular insights and clinical applications. Pathology, research and practice. 2025; 269:155945.
- 22.
22. Khan SL, Siddiqui FA. Beta-Sitosterol: As Immunostimulant, Antioxidant and Inhibitor of SARS-CoV-2 Spike Glycoprotein. Arch Pharmacol Ther. 2020;2(1):12-16.
- 23.
23. Shaheen A, Fida H, Akhmedov S, Rasulbek E, Ataullaev Z. In Silico Study of Alkaloids as Potential Cyclin-Dependent Kinase (CDK) Inhibitors. J Pharm Sci Comput Chem. 2025;1(4):324–35.
- 24.
24. Haque MA, Marathakam A, Rana R, Almehmadi SJ, Tambe VB, Charde MS, et al. Fighting Antibiotic Resistance: New Pyrimidine-Clubbed Benzimidazole Derivatives as Potential DHFR Inhibitors. Molecules. 2023;28(2):501.
- 25.
25. Abubaker MA, Omari KW, Baki ZA, Shakya PR, Hasan HMA, Saleh SM, et al. Computational Evaluation of Cryptolepine and Tryptanthrin as Potential α -Glucosidase Inhibitors. J Pharm Sci Comput Chem. 2025;1(4):336–46.
- 26.
26. Tamboli AS, D. Tayade S. In-Depth Investigation of Berberine and Tropane through Computational Screening as Possible DPP-IV inhibitors for the Treatment of T2DM. J Pharm Sci Comput Chem. 2025;1(1):1–11.
Suggested & Related Publications
Articles in related pharmaceutical, biomedical, and life sciences research on PharmSciGate
Computational Study of Alkaloids Targeting O-GlcNAc Transferase as Antidiabetic Agents
Pardaev Jamshid; Umida Sadikova
O-GlcNAc Transferase (OGT) plays a pivotal role in glucose metabolism and insulin signaling, making it an attractive therapeutic target for the management of diabetes mellitus. In the present study, a comprehensive in silico approach was employed to investigate the inhibitory potential of selected alkaloids against human OGT, with an emphasis on their binding affinity and pharmacokinetic suitability. Molecular docking analysis was performed using AutoDock Vina to elucidate the interaction patterns between the selected compounds and the active site of OGT. The docking results revealed that berberine exhibited the strongest binding affinity (−7.8 kcal/mol), slightly surpassing that of the native ligand (−7.7 kcal/mol), and formed stable hydrogen bonding and hydrophobic interactions with key catalytic residues such as LYS898, ASN838, and PRO559. In contrast, castanospermine and swainsonine showed comparatively weaker binding affinities, attributed to limited interaction networks within the binding pocket. To further assess the drug development potential of the studied compounds, in silico ADMET analysis was carried out using SwissADME and ADMETlab 3.0. Berberine demonstrated favorable physicochemical properties, superior drug-likeness (highest QED score), and acceptable absorption and toxicity profiles compared to the native ligand and other alkaloids. Although potential cytochrome P450 interactions and moderate bioaccumulation were predicted for berberine, its overall pharmacokinetic profile was well balanced. Collectively, the integrated docking and ADMET results highlight berberine as a promising lead alkaloid targeting OGT, warranting further in vitro and in vivo validation for its potential development as an antidiabetic agent.
Drug repurposing of some US FDA-approved drugs using Binding strength Studies for the Treatment of Methicillin-resistant Staphylococcus aureus Infection
Roy, Dibakar
Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug-resistant bacterial pathogen responsible for severe infections worldwide. The increasing resistance of MRSA to conventional antibiotics has created an urgent need for new therapeutic strategies. Drug repurposing of US FDA-approved drugs offers a promising approach to identify alternative anti-MRSA agents while reducing the time and cost associated with traditional drug discovery. In this study, computational Binding strength analysis was performed to evaluate the inhibitory potential of selected compounds against important MRSA target enzymes, including thioredoxin reductase 1, proton motive force protein, and penicillin-binding protein 2a (PBP2a). Molecular docking results demonstrated strong interactions between the ligands and the active sites of the selected enzymes. The native ligand NL_3QFB showed the strongest Binding strength toward thioredoxin reductase 1 with a docking score of −12.2 kcal/mol, while the reference drug Auranofin exhibited −7.8 kcal/mol. For the proton motive force protein, NL_9U6O displayed a docking score of −7.4 kcal/mol, comparable to Niclosamide (−7.5 kcal/mol). Similarly, NL_6Q9N showed strong interaction with PBP2a with a docking score of −8.6 kcal/mol, whereas Afamelanotide showed weaker binding (−1.9 kcal/mol). ADMET analysis indicated acceptable physicochemical and pharmacokinetic properties for several compounds. Overall, the findings suggest that the investigated ligands demonstrate promising Binding capability and favorable drug-like properties against MRSA target enzymes. However, further experimental validation is required to confirm their therapeutic potential.
Green Chemistry-Based Extraction, Phytochemical Screening, and Evaluation of Anti-Inflammatory Activity of Aerva lanata
Alshahrani, Malath Saeed; Alshahrani, Wajan Khalid; A Assiri, Sara Abdullah; Alasmari, Waad Oudah; Alqahtani, Arwa Ali
Green chemistry has emerged as an important approach in natural product research because it promotes environmentally friendly extraction techniques and minimizes the use of hazardous solvents. The present study investigated the green chemistry-based extraction, phytochemical screening, (PS) and evaluation of the anti-inflammatory activity of Aerva lanata, a medicinal plant widely used in traditional medicine. The plant material was collected from the Buldhana region of Maharashtra, India, shade-dried, powdered, and subjected to hydroalcoholic extraction using the maceration method to obtain the crude extract. Preliminary PS was performed using standard qualitative tests, which revealed the presence of several important phytoconstituents including alkaloids, flavonoids, phenolic compounds, tannins, saponins, terpenoids, and steroids, while glycosides were present in minor amounts. These phytochemicals are known for their significant pharmacological activities, particularly antioxidant and anti-inflammatory effects. The anti-inflammatory potential of the extract was evaluated using an in vitro protein denaturation inhibition assay at concentrations of 100–500 µg/mL. The results demonstrated a concentration-dependent increase in inhibition, with values of 10.4%, 15.8%, 17.6%, 28.9%, and 39.7% at concentrations of 100, 200, 300, 400, and 500 µg/mL, respectively. In comparison, the standard drug diclofenac sodium exhibited inhibition values of 40.2%, 55.6%, 69.4%, 82.1%, and 91.5% at the same concentrations. These findings indicate that Aerva lanata possesses notable AI, which may be attributed to the synergistic effects of its phytochemical constituents. Overall, the study supports the traditional medicinal use of Aerva lanata and highlights its potential as a promising natural source for developing safer anti-inflammatory therapeutic agents
Full-Text Access
Journal of PhytoPharmaceutical and Advanced Chemistry
An international, peer-reviewed journal integrating phytopharmaceutical sciences, natural products, and advanced pharmaceutical chemistry.
This peer-reviewed publication is indexed directly from the publisher repository adhering to Open Archives Initiative (OAI-PMH) metadata standards, Crossref DOI schema, and Google Scholar Highwire Press protocols.