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

• NPRs are hunted by a structure-based drug discovery (SBDD) algorithm carried on an intensive supercomputer “DEGIMA”.
• NPRs bind to PrPC using surface plasmon resonance analysis and thermal shift assay.
• NPRs bind to PrPC by van der Waals interaction using the fragment molecular orbital calculation.
• NPRs suppress PrPSc levels and aggresomes in persistently prion-infected cells.
• NPRs inhibit PrPSc levels and microglia activation in prion-infected mice brain.
• In silico drug discovery using SBDD enable to develop the available therapeutic agents for prion disease.None of effective and efficient therapeutic agents for prion disease is available. In this manuscript, we describe the drug discovery against prion disease using novel screening system. In this system, we performed docking simulation using original calculation system, termed DEGIMA supercomputer, and searched candidate compounds as anti-prion drug from among the many chemical compounds library. The compounds directly interacted with recombinant prion protein, and drastically reduced abnormal form prion protein in the prion-infected cells and the brain of illness mice. This drug discovery may be useful for the therapeutic development to cure conformational disorders.

The accumulation of abnormal prion protein (PrPSc) converted from the normal cellular isoform of PrP (PrPC) is assumed to induce pathogenesis in prion diseases. Therefore, drug discovery studies for these diseases have focused on the protein conversion process. We used a structure-based drug discovery algorithm (termed Nagasaki University Docking Engine: NUDE) that ran on an intensive supercomputer with a graphic-processing unit to identify several compounds with anti-prion effects. Among the candidates showing a high-binding score, the compounds exhibited direct interaction with recombinant PrP in vitro, and drastically reduced PrPSc and protein-aggresomes in the prion-infected cells. The fragment molecular orbital calculation showed that the van der Waals interaction played a key role in PrPC binding as the intermolecular interaction mode. Furthermore, PrPSc accumulation and microgliosis were significantly reduced in the brains of treated mice, suggesting that the drug candidates provided protection from prion disease, although further in vivo tests are needed to confirm these findings. This NUDE-based structure-based drug discovery for normal protein structures is likely useful for the development of drugs to treat other conformational disorders, such as Alzheimer's disease.