Structure-Based Drug Discovery for Prion Disease Using a Novel Binding Simulation.

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Prion diseases are linked to the accumulation of abnormal prion protein (PrPSc) from normal cellular PrP (PrPC).
• Current drug discovery efforts focus on inhibiting the conversion of PrPC to PrPSc.

Purpose of the Study:

• To identify novel compounds with anti-prion activity using a structure-based drug discovery approach.
• To investigate the mechanism of action and therapeutic potential of identified compounds against prion diseases.

Main Methods:

• Utilized a structure-based drug discovery algorithm (NUDE) on a supercomputer to screen compounds.
• Performed in vitro assays with recombinant PrP and prion-infected cells.
• Conducted fragment molecular orbital calculations to analyze binding interactions.
• Evaluated compound efficacy in a mouse model of prion disease.

Main Results:

• Identified several compounds with high binding scores that directly interact with recombinant PrP.
• Demonstrated significant reduction in PrPSc and protein-aggresomes in prion-infected cells.
• Fragment molecular orbital analysis revealed van der Waals interactions as key for PrPC binding.
• Observed reduced PrPSc accumulation and microgliosis in the brains of treated mice.

Conclusions:

• The identified compounds show direct anti-prion effects by interacting with PrP.
• NUDE-based drug discovery is effective for targeting protein conformational disorders.
• Further in vivo studies are warranted to confirm therapeutic efficacy for prion diseases and potentially other conformational disorders like Alzheimer's disease.