Integration of Synthetic Organic Chemistry and <i>in silico</i> Drug Discovery - Lead Discovery of Renin Inhibitors and <i>O</i>-GlcNAcase Inhibitors

<p>Synthetic organic chemistry is a core technology of drug discovery, but combined with in silico technology which consists of molecular modeling and/or informatics using computational methods, it can be expected to accelerate drug discovery research and increase the success rate for developing a new drug. However, in silico technology cannot create new drugs by itself, and its integration with organic chemistry is necessary. In this paper, we describe drug discovery research that effectively integrates organic chemistry and in silico technology to develop synthetic strategies and efficiently create a novel lead compound or in vivo tool.</p><p>The first study is a drug discovery research for renin inhibitors. We applied a fragment-based approach to discover high-quality hit compounds through comprehensive analysis of virtual library and high throughput library synthesis. The subsequent rational structure-based drug design approach focusing on hotspots enhanced the renin inhibitory activity dramatically and then discovered a novel lead compound with moderate bioavailability in rats. The second study is a drug discovery research for O-GlcNAcase (OGA) inhibitors. We identified a potent compound by virtual screening and optimized the hit chemical series utilizing a docking model, pocket analysis, and molecular dynamics (MD) to improve ligand lipophilicity efficiency (LLE), which resulted in a novel OGA inhibitor demonstrating the increase of O-GlcNAcylated protein level in cells with suitable pharmaceutical properties and brain permeability.</p><p>These studies provided not only high-quality lead compounds but also essential information that can be used to strategically promote drug discovery research to both synthetic organic chemists and computational chemists.</p>