In silico study of structure-based screening of inhibitors to block PrPC Conversion and amyloid aggregation

Kamakshi Ruhela¹Subham unknown¹Shailendra Shanker Maurya²Hemlata Dwivedi-Agnihotri¹Sumit K Chaturvedi^1*

• ¹Department of Biophysics, University of Delhi, India, India
• ²Chromatin Architecture Laboratory, Department of Hematology (SCRC), Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raibareli Road, Lucknow, INDIA, Lucknow, India

Prion diseases are a group of progressive and fatal neurodegenerative diseases, caused by the transformation of cellular prion protein (PrPC) into a misfolded pathogenic isoform (PrPSc). Several strategies have been proposed to mitigate different stages of prion propagation and aggregation. One such approach involves limiting the availability of PrPᶜ substrate for misfolding. Various compounds have been shown to inhibit the conversion process; however, no compounds have been identified that are potentially effective in curing prion diseases. Therefore, identifying novel inhibitors targeting key stages of PrP misfolding is essential. This study aims to identify potential anti-prion compounds through a comparative in silico approach, which involves molecular docking, pharmacophore-based modelling, and ADMET analysis, using known inhibitors (such as anle138b, GN8, and resveratrol). Through this approach, we have identified some novel compounds that possess the potential to cure prion diseases. Molecular docking results revealed critical protein-ligand interactions, which were later used to construct pharmacophore models. These models directed virtual screening to find structurally and functionally analogous compounds. Drug-likeness and pharmacokinetic properties were evaluated through ADMET profiling. Furthermore, we also analysed whether these screened compounds could reproduce the key interactions seen in known inhibitors, which led to the identification of three potential anti-prion compounds. It reflects the potential of pharmacophore-based high-throughput virtual screening when discovering structurally diverse compounds with similar target profiles. Further validation through molecular dynamics simulations and experimental assays is necessary to confirm their efficacy and advance therapeutic development against prion diseases.