Flavonoids as Strong Inhibitors of MAPK3: A Computational Drug Discovery Approach

Abstract

Background. Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer. Objectives. The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy. Methods. A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor’s active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations. Results. Kaempferol 3-rutinoside-4′-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor’s active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations. Conclusion. The present study suggests that kaempferol 3-rutinoside-4′-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.

Elucidating the anti-cancer potential of Cinnamomum tamala essential oil against non-small cell lung cancer: A multifaceted approach involving GC-MS profiling, network pharmacology, and molecular dynamics simulations

“…HIF-1α overexpression leads to an increase in the invasion of human lung adenocarcinoma cells. MAPK3 protein belongs to the MAPK family and is associated with several cancer cells initiation, progression, and migration, including lung, thyroid, liver and gastric cancers [ 40 ]. IL6 has been found to promote metastasis in A549 cells and BALB/c lung metastasis mice model [ 41 ].…”

“…Previously 17-β estradiol and deoxysappanone B 7,3′-dimethyl ether acetate formed hydrophobic interaction with LEU173 residue of MAPK3 [ 57 ]. Similarly, in the complex involving kaempferol 3-rutinoside-4′-glucoside and MAPK3, there was also evidence of hydrophobic interaction with the ILE48 residue of MAPK3 [ 58 ]. The binding free energy of MAPK3 with cinnamaldehyde was −5.5 kcal/mol.…”

Exploring potent aldose reductase inhibitors for anti-diabetic (anti-hyperglycemic) therapy: integrating structure-based drug design, and MMGBSA approaches

“…ADFR employed flexible docking with high accuracy for each compound against aldose reductase, utilizing the AutoDock four scoring function ( Aly et al, 2023 ). Finally, from in-house and commercial databases (ZINC and the South African Natural Compounds Database), the top two hits were finalized from each database on the basis of docking score and binding interaction using Schrodinger Maestro and Pymol software and carried out for MD simulation ( Maya Díaz, 2023 ; Taherkhani et al, 2023 ).…”

Positive effects of rutin on female reproduction

“…These observations suggest that the stimulatory action of rutin on ovaries could be mediated by promotion of proliferation and suppression of apoptosis through changes in PTEN/FOXO3a pathway. The stimulatory action of rutin on ovarian cells via up-regulation of their proliferation and down-regulation of their apoptosis was confirmed by ability of rutin to inhibit proliferation of cultured human ovarian cancer cells (Luo et al, 2008;Wang et al, 2022) probably via MAPK-3-dependent mechanisms (Taherkhani et al, 2023), as well as to promote accumulation of PCNA and to suppress accumulation of bax in cultured porcine ovarian granulosa cells (Sirotkin et al, 2020,b). On the other hand, in other similar experiments, rutin was able to increase viability of cultured porcine ovarian granulosa cells without changes in these markers of proliferation and mitochondrial apoptosis (Sirotkin et al, 2021) indicating that in some conditions rutin could support ovarian cell functions via intracellular mechanisms not related to proliferation and mitochondrial apoptosis.…”

“…For example, it can down‐regulate the pro‐inflammatory transcription factor NF‐kB, proinflammatory cytokines interleukins‐1b and ‐18, activate antioxidant enzymes and proliferation‐promoting mitogen‐activated protein kinase‐lipid kinase and tyrosine kinase‐dependent signalling pathways, downregulation of mRNA expression of proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, activation of anti‐proliferative and pro‐apoptotic transcription factor p53, induction of autophagy, and restoration of the activities of mitochondrial complex enzymes (Enogieru et al., 2018; Farha et al., 2020; Imani et al., 2021; Nouri et al., 2020; Simunkova et al., 2019; Yi, 2018). There are evidence that rutin can suppress proliferation of cancer cells by binding and inactivation of mitogen‐activated protein kinase 3 (MAPK‐3), the key promoter of the cell cycle (Taherkhani et al., 2023).…”