Logical design of anti-prion agents using NAGARA

Area of Science:

• Computational chemistry and drug discovery
• Structural biology and prion diseases
• Bioinformatics and cheminformatics

Background:

• Accelerating logical drug design is crucial for developing new therapeutics.
• Stabilizing the cellular form of prion protein (PrP(C)) is a key strategy for treating prion diseases.
• Existing computational tools lack integration for comprehensive drug design workflows.

Purpose of the Study:

• To introduce NAGARA, a novel PyMOL plugin designed to streamline the drug design process.
• To demonstrate NAGARA's capability in identifying small compounds, specifically medical chaperones (MCs), that stabilize PrP(C).
• To showcase the integration of various computational and experimental methods within a single platform for drug discovery and optimization.

Main Methods:

• Development of the NAGARA platform integrating docking simulation (DS), molecular dynamics (MD) simulation, and quantum chemistry (QC) calculations.
• Application of NAGARA for large-scale parallel computing with a user-friendly graphical interface.
• Validation of computational predictions using experimental methods such as Western blotting (WB), surface plasmon resonance (SPR), and nuclear magnetic resonance (NMR).

Main Results:

• NAGARA successfully integrated DS, MD, and QC, enabling efficient drug design and lead optimization.
• The platform facilitated the discovery of two novel compounds and tegobuvir (TGV) with anti-prion activities, stabilizing PrP(C).
• Computational predictions of binding profiles were consistent with experimental SPR and NMR data, and free energy analyses confirmed stabilization of PrP(C) conformation.

Conclusions:

• NAGARA significantly accelerates the drug design pipeline by unifying diverse computational and experimental approaches.
• The identified compounds, including the approved drug TGV, show potential for treating prion diseases by stabilizing PrP(C).
• Further optimization of lead compounds is feasible using NAGARA's integrated QC and recursive validation methods.