title: Logical design of anti-prion agents using NAGARA.
abstract: To accelerate the logical drug design procedure, we created the program "NAGARA," a plugin for PyMOL, and applied it to the discovery of small compounds called medical chaperones (MCs) that stabilize the cellular form of a prion protein (PrP(C)). In NAGARA, we constructed a single platform to unify the docking simulation (DS), free energy calculation by molecular dynamics (MD) simulation, and interfragment interaction energy (IFIE) calculation by quantum chemistry (QC) calculation. NAGARA also enables large-scale parallel computing via a convenient graphical user interface. Here, we demonstrated its performance and its broad applicability from drug discovery to lead optimization with full compatibility with various experimental methods including Western blotting (WB) analysis, surface plasmon resonance (SPR), and nuclear magnetic resonance (NMR) measurements. Combining DS and WB, we discovered anti-prion activities for two compounds and tegobuvir (TGV), a non-nucleoside non-structural protein NS5B polymerase inhibitor showing activity against hepatitis C virus genotype 1. Binding profiles predicted by MD and QC are consistent with those obtained by SPR and NMR. Free energy analyses showed that these compounds stabilize the PrP(C) conformation by decreasing the conformational fluctuation of the PrP(C). Because TGV has been already approved as a medicine, its extension to prion diseases is straightforward. Finally, we evaluated the affinities of the fragmented regions of TGV using QC and found a clue for its further optimization. By repeating WB, MD, and QC recursively, we were able to obtain the optimum lead structure.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Biao
authors.initials: B
authors.lastname: Ma
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Fukuoka
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Department of Gene and Development, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: kuwata@gifu-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011328:Prions / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011687:Purines / Q000737:chemistry*; D011724:Pyridazines / Q000737:chemistry*; D011789:Quantum Theory; D012984:Software
chemical_list: D011328:Prions; D011687:Purines; D011724:Pyridazines; C571890:tegobuvir
keywords: Anti-prion agent; Logical drug design; NAGARA; Prion; Quantum chemistry; Tegobuvir