Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach

Abstract

Cancer continues to be leading cause of death globally, with nearly 7 million deaths per year. Despite significant progress in cancer research and treatment, there remain several challenges to overcome, including drug resistance, the presence of cancer stem cells, and high interstitial fluid pressure in tumors. To tackle these challenges, targeted therapy, specifically targeting HER2 (Human Epidermal Growth Factor Receptor 2) as well as EGFR (Epidermal Growth Factor Receptor), is considered a promising approach in cancer treatment. In recent years, phytocompounds have gained recognition as a potential source of chemopreventive and chemotherapeutic agents in tumor cancer treatment. Phytocompounds are compounds derived from medicinal plants that have the potential to treat and prevent cancer. This study aimed to investigate phytocompounds from Prunus amygdalus var amara seeds as inhibitors against EGFR and HER2 enzymes using in silico methods. In this study, fourteen phytocompounds were isolated from Prunus amygdalus var amara seeds and subjected to molecular docking studies to determine their ability to bind to EGFR and HER2 enzymes. The results showed that diosgenin and monohydroxy spirostanol exhibited binding energies comparable to those of the reference drugs, tak-285, and lapatinib. Furthermore, the drug-likeness and ADMET predictions, performed using the admetSAR 2.0 web-server tool, suggested that diosgenin and monohydroxy spirostanol have similar safety and ADMET properties as the reference drugs. To get deeper insight into the structural steadiness and flexibility of the complexes formed between these compounds and theEGFR and HER2 proteins, molecular dynamics simulations were performed for 100 ns. The results showed that the hit phytocompounds did not significantly affect the stability of the EGFR and HER2 proteins and were able to form stable interactions with the catalytic binding sites of the proteins. Additionally, the MM-PBSA analysis revealed that the binding free energy estimates for diosgenin and monohydroxy spirostanol is comparable to the reference drug, lapatinib. This study provides evidence that diosgenin and monohydroxy spirostanol may have the potential to act as dual suppressors of EGFR and HER2. Additional in vivo and in vitro research are needed to certify these results and assess their efficacy and safety as cancer therapy agents. The experimental data reported and these results are in agreement.

Antioxidant and antibacterial activities of 5-mercapto(substitutedthio)-4-substituted-1,2,4-triazol based on nalidixic acid: A comprehensive study on its synthesis, characterization, and In silico evaluation

“…S1 ). This value falls well within the acceptable range for utilizing docking as a predictive tool for assessing the binding affinity of small molecules [ 41 , [46] , [47] , [48] ]. These findings not only affirm the reliability of the docking process parameters but also underscore the utility of docking as a robust tool for predicting the binding affinity of the tested compounds ( 3b , 4f , 4h , 4j , and 4o ) against the FabH enzyme.…”

“…The resulting structures were saved in PDB format. Additionally, any missing amino acids in the target structures were integrated using the YASARA web-server tool [ [40] , [41] , [42] ]. Titratable amino acid groups' ionization states at pH 7.0 were calculated through the use of H++ web-server tool [ [41] , [42] , [43] ].…”

“…Additionally, any missing amino acids in the target structures were integrated using the YASARA web-server tool [ [40] , [41] , [42] ]. Titratable amino acid groups' ionization states at pH 7.0 were calculated through the use of H++ web-server tool [ [41] , [42] , [43] ]. Finally, AutoDock Tools version 1.5.6 tools transformed these outputs into PDBQT format by adding polar hydrogen atoms and Kollman charges [ 44 ].…”

“…An essential part of this validation involves calculating the Root Mean Square Deviation (RMSD) between the two ligand positions. An RMSD value below 2 Å is deemed acceptable [ 41 , [46] , [47] , [48] ], indicating a minimal deviation between the predicted and actual ligand configurations. This criterion ensures our docking approach can reliably replicate known ligand interactions, thereby enhancing the credibility of our simulation outcomes.…”

Steroidal Saponins: Naturally Occurring Compounds as Inhibitors of the Hallmarks of Cancer

“…Molecular docking studies suggest that the binding affinity of the three compounds to the aforementioned receptors is higher than the binding of tyrosine kinase inhibitor erlotinib [30]. In another in silico study, diosgenin and monohydroxy spirostanol derived from Prunus dulcis seeds exhibited binding affinities to EGFR and Human Epidermal Growth Factor Receptor 2 (HER2) comparable to cancer drugs such as tak-285 and lapatinib [31].…”