مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
In silico screening of inhibitors against human dihydrofolate reductase to identify potential anticancer compounds
In silico screening of inhibitors against human dihydrofolate reductase to identify potential anticancer compounds
Asma Soofi,1,*
1. University of Tehran Department of Physical Chemistry
Introduction: In all species, dihydrofolate reductase (DHFR) is an essential enzyme that regulates the cellular amount of tetrahydrofolate. Human DHFR (hDHFR) activity inhibition results in tetrahydrofolate depletion and cell death. This property has made hDHFR a therapeutic target for cancer. Methotrexate is a wellknown hDHFR inhibitor, but its administration has shown some light to severe adverse effects. Therefore, we aimed to find new potential hDHFR inhibitors using structure-based virtual screening, ADMET prediction, molecular docking, and molecular dynamics simulations. Here, we used the PubChem database to find all compounds with at least 90% structural similarity to known natural DHFR inhibitors. To explore their interaction pattern and estimate their binding affinities, the screened compounds (2023) were subjected to structure-based molecular docking against hDHFR
Methods: Here, compounds having the most remarkable structural resemblance to known natural DHFR inhibitors (Bastadin, Puupehenone, Sanguinarine, and Curcumin) were downloaded from the PubChem database and subjected to structure-based molecular docking against hDHFR. The physicochemical and ADMET characteristics of selected compounds were used to filter them out. Molecular docking was performed to investigate the binding affinity and conformation of the selected compounds in the active site of hDHFR. Finally, MD simulations were applied to assess conformational changes, stability, and
the interaction of hDHFR in combination with the chosen compounds compared to MTX. Two compounds were identified as putative hDHFR inhibitors based on the findings.
Results: The fifteen compounds that showed higher binding affinity to the hDHFR than the reference compound (methotrexate) displayed important molecular orientation and interactions with key residues in the enzyme’s active site. These compounds were subjected to Lipinski and ADMET prediction. PubChem CIDs: 46886812 and 638190 were identified as putative inhibitors. In addition, molecular dynamics simulations revealed that the binding of compounds (CIDs: 46886812 and 63819) stabilized the hDHFR structure and caused minor conformational changes. Our findings suggest that two compounds (CIDs: 46886812 and 63819) could be promising potential inhibitors of hDHFR in cancer therapy.
Conclusion: In conclusion, the findings of this research demonstrated that two hit compounds (CIDs: 46886812 and 638190) successfully displayed appropriately in silico binding patterns in the active site of hDHFR. Additionally, their acceptable ADMET properties and drug-likeness increase their potential to be developed as anticancer drugs. Finally, MD simulations proved the stability of compounds with hDHFR. Future in vitro and in vivo investigations will be necessary to confirm these two compounds as new hDHFR inhibitors for cancer treatment.