We explored the potential of bioactive phytochemicals as inhibitors of PDGFRβ through a multitier virtual screening approach, involving molecular docking, ADMET analysis, PASS analysis, and all-atom MD simulations followed by essential dynamics. The results demonstrate that the identified phytochemical hits have the potential to show significant binding affinities with PDGFRβ and possess favorable ADMET properties, making them promising candidates for further investigation in drug development. Initially, the molecular docking analysis identified the top 30 phytochemical hits with appreciable binding affinities to PDGFRβ. These compounds showed calculated binding energies of ≤ − 9.5 kcal/mol, indicating strong interactions with the receptor. The selection of these compounds based on Lipinski's rule of five ensures their drug-like properties and increases the likelihood of success in the drug development process.
ADMET analysis is an essential step in drug discovery to assess the pharmacokinetic properties and potential toxicity of candidate compounds [59]. We evaluated the ADMET properties of the selected phytochemicals and identified four compounds with favorable properties for absorption, distribution, metabolism, excretion, and low toxicity. Importantly, these compounds were devoid of any PAINS patterns, indicating that they are not likely to interfere with the assay results during drug screening. This finding is encouraging as it suggests that the identified compounds have the potential to progress further in the drug discovery pipeline. The investigation of biological properties of phytochemicals through PASS analysis provides valuable insights into their potential activities [35]. The analysis revealed that two compounds, Genostrychnine and Chelidonine, exhibited favorable biological properties, acting as antineoplastic alkaloids, platelet adhesion inhibitors, and apoptosis agonists. These properties indicate that these compounds may have potential in anticancer activities and inhibiting kinase activity, which is highly relevant for PDGFRβ inhibition.
Further, the interaction analysis provided detailed insights into how Genostrychnine and Chelidonine interacted with the active site of PDGFRβ. The analysis demonstrated that both compounds formed strong interactions with the Asp826 residue, a crucial region for the functional activity of the kinase. The complementarity of these compounds within the deep binding pocket of PDGFRβ suggests their potential as ATP-competitive inhibitors of the PDGFRβ kinase.
MD simulations are valuable tools for studying the stability and dynamics of protein-ligand complexes over time [60, 61]. The simulations performed in this study revealed that both PDGFRβ-Genostrychnine and PDGFRβ-Chelidonine complexes exhibited good stability. The RMSD, RMSF, Rg, and SASA analyses indicated that the binding of Genostrychnine and Chelidonine to PDGFRβ could lead to stable complexes, with minor fluctuations in some regions. The hydrogen bonding analysis also suggested that both complexes had stable intramolecular and intermolecular H-bonds. The PCA and FEL analyses provided further insights into the conformational behavior of the complexes and indicated their potential thermodynamic stability.
Overall, the results presented here are compelling and offer valuable information about the potential of the identified phytochemical hits as PDGFRβ inhibitors. The combination of molecular docking, ADMET analysis, PASS analysis, and all-atom MD simulations provides a comprehensive assessment of the identified compounds, allowing us to make informed decisions on which compounds to prioritize for further experimental studies. This study contributes to the field of drug discovery and development and offers potential avenues for designing novel PDGFRβ inhibitors with the identified phytochemicals as starting points. However, it is essential to perform experimental validations to confirm the findings and assess the biological activities and inhibitory effects of Genostrychnine and Chelidonine in vitro and in vivo.