In silico analysis of small molecule compounds based on pharmacophore- and backbone-leaping peroxiredoxin 1 (PRDX1) inhibitors

Abstract

Abnormal expression of PRDX has been found to play a significant role in the growth of colorectal cancer and other types of tumors. Despite the identification of several PRDX1 inhibitory compounds in recent years, none of them have been utilized in clinical treatments. Therefore, we conducted a virtual screening of 210,331 small molecules from the SPECS library using PRDX1 and multiple methods. From this screening, we identified 13 compounds with the highest scores from the molecular docking analysis. To further validate the accuracy of our pharmacophore model, we constructed a structure-based pharmacophore model and analyzed the receiver operating characteristic curve (ROC curve). Through this process, we selected nine compounds using skeleton jumping and virtual screening based on the highest pharmacophore model scores. Subsequently, we examined the ADMET properties of these nine compounds to assess their drug-forming potential, resulting in three compounds with the best drug properties. Finally, we assessed the binding stability of these three candidate molecules to proteins using molecular dynamics and MM-PBSA calculations. After a comprehensive evaluation, we found that compounds 6 and 9 formed stable complexes with PRDX1 proteins and could potentially serve as competitive inhibitors of PRDX1 substrates.

Communicated by Ramaswamy H. Sarma

Keywords:

• PRDX1
• pharmacophore modeling
• skeleton jump
• virtual screening
• molecular dynamics simulation
• MM-PBSA calculations

Acknowledgement

We thank the Public Service Platform of South China Sea for R&D Marine Biomedicine Resources for support.

Author contributions

LX Luo conceived the study; NY Zheng, HT Tan and TL Lai performed docking studies, ADMET studies, molecular dynamics and simulations; manuscript editing; LX Luo and NY Zheng drafted manuscript. LX Luo and ZN Huang reviewed the paper and provided comments. All authors contributed to this article and approved the submitted version.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

This research was funded by the Key Discipline Construction Project of Guangdong Medical University(4SG23004G).