Screening and Analysis of Possible Drugs Binding to PDGFRα: A Molecular Modeling Study

by Selleckchem | Oct 09 2023

The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in 5 independent databases/libraries implemented in the MTiOpenScreen web server. After the selection of 27 compounds, a structural analysis of the obtained complexes was performed. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also performed to understand the physicochemical properties of identified compounds to increase affinity and selectivity for PDGFRα. Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib, and Imatinib showed higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products included in this group, such as curcumin, luteolin, and epigallocatechin gallate (EGCG), showed sub-micromolar affinities. Although experimental studies are mandatory to fully understand the mechanisms behind PDGFRα inhibitors, the structural information obtained through this study could provide useful insight into the future development of more effective and targeted treatments for PDGFRα-related diseases, such as cancer and fibrosis.

Comments:

The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor that plays a crucial role in various physiological and pathological processes. In this study, the aim was to identify potential ligands or gather new information to design effective drugs targeting PDGFR. To achieve this, an initial interaction screening was conducted using the MTiOpenScreen web server, which involved approximately 7200 drugs and natural compounds from five independent databases/libraries.

Following the screening, 27 compounds were selected for further analysis. The obtained complexes of these compounds with the human intracellular PDGFRα were subjected to structural analysis. Additionally, three-dimensional quantitative structure-activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were performed to gain insights into the physicochemical properties of the identified compounds, aiming to enhance their affinity and selectivity for PDGFRα.

Among the 27 compounds, four drugs, namely Bafetinib, Radotinib, Flumatinib, and Imatinib, exhibited higher affinity for the PDGFRα receptor, with nanomolar range binding. On the other hand, natural products such as curcumin, luteolin, and epigallocatechin gallate (EGCG) displayed sub-micromolar affinities.

It is important to note that experimental studies are necessary to fully comprehend the mechanisms underlying PDGFRα inhibition by these compounds. Nonetheless, the structural information obtained from this study offers valuable insights for the future development of more effective and targeted treatments for PDGFRα-related diseases, including cancer and fibrosis.