title: Novel approach of fragment-based lead discovery applied to renin inhibitors.
abstract: A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3SP(S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3SPsites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin's active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: michiko.tawada@takeda.com.
authors.forename: Michiko
authors.initials: M
authors.lastname: Tawada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Shinkichi
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.affiliation: Takeda California, Inc., 10410, Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.affiliation: Takeda California, Inc., 10410, Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Behnke
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kuroita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tomimoto
mesh_terms: D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors
keywords: Crystal structure; Fragment-based drug discovery (FBDD); High-throughput synthetic chemistry; Renin inhibitor; Structure-based drug design (SBDD)