title: A highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization.
abstract: We disclose herein the rapid discovery of the first highly potent (Ki = 7.7 nM) non-nucleoside adenosine deaminase (ADA) inhibitor based on the rational hybridization of two structurally distinct leads. Two micromolar inhibitors were discovered by a parallel rational design and random screening program, and individual crystal structures of bovine ADA in complexation with these inhibitors revealed several unknown binding sites and distinct binding modes. Using this information as the starting point, highly effective lead hybridization was achieved in only two structure-based drug design iterations. The conceptual approach illustrated by this example promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the overall efficiency and speed of drug discovery.
authors.affiliation: Medicinal Chemistry Research Laboratories, Basic Research Laboratories, and Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terasaka
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Masako
authors.initials: M
authors.lastname: Kuno
authors.forename: Isao
authors.initials: I
authors.lastname: Nakanishi
mesh_terms: D058892:Adenosine Deaminase Inhibitors; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058892:Adenosine Deaminase Inhibitors; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D009705:Nucleosides; D013844:Thiazoles