Structure-Based Design and Synthesis of Non-Nucleoside, Potent, and Orally Bioavailable Adenosine Deaminase Inhibitors

Terasaka, Tadashi; Okumura, Hiroyuki; Tsuji, Kiyoshi; Kato, Takeshi; Nakanishi, Isao; Kinoshita, Takayoshi; Kato, Yasuko; Kuno, Miyuki; Seki, Nobuo; Naoe, Yoshinori; Inoue, Takeshi; Tanaka, Kohichiro; Nakamura, Katsuya

doi:10.1021/jm0499559

Cited by 23 publications

(44 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An established research base exists in inhibition of the activity of this enzyme class (EC 3.5.4.4) and potent inhibitors, both nucleoside-like (e.g., DCF) and non-nucleoside-like [e.g., erythro-9-(2-hydroxy-3-nonyl)adenine], are well characterized, providing the opportunity to piggyback on these molecules to aid in the drug design process. Furthermore, several inhibitor-bound structures of murine 11,12 and bovine 14,15,[21][22][23][24] ADAs are available for comparison of the active-site environments between mammalian and parasite enzymes.…”

Section: Methodsmentioning

confidence: 99%

Structures of Substrate- and Inhibitor-Bound Adenosine Deaminase from a Human Malaria Parasite Show a Dramatic Conformational Change and Shed Light on Drug Selectivity

Larson

Deng

Krumm

et al. 2008

Journal of Molecular Biology

View full text Add to dashboard Cite

Plasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes.

show abstract

Section: Methodsmentioning

confidence: 99%

Structures of Substrate- and Inhibitor-Bound Adenosine Deaminase from a Human Malaria Parasite Show a Dramatic Conformational Change and Shed Light on Drug Selectivity

Larson

Deng

Krumm

et al. 2008

Journal of Molecular Biology

View full text Add to dashboard Cite

show abstract

“…Actually, all substrate analogues such as HDPR, which almost fully occupy the hydrophilic S0 subsite, induce the closed form. Furthermore, we observed that introduction of the methyl group into the S0 subsite leads to an ∼30 times higher binding affinity, but the same introduction into the F2 subsite yields little activity (8,9). Furthermore, in complexes with the closed form, the W4 position is empty (4, 6, 26).…”

Section: Structural Analysis Of Nonligated Ada and A Fr104783-ada Commentioning

confidence: 96%

Structural Basis of Compound Recognition by Adenosine Deaminase

et al. 2005

Self Cite

View full text Add to dashboard Cite

Structural snapshots corresponding to various states enable elucidation of the molecular recognition mechanism of enzymes. Adenosine deaminase has two distinct conformations, an open form and a closed form, although it has so far been unclear what factors influence adaptation of the alternative conformations. Herein, we have determined the first nonligated structure as an initial state, which was the open form, and have thereby rationally deduced the molecular recognition mechanism. Inspection of the active site in the nonligated and ligated states indicated that occupancy at one of the water-binding positions in the nonligated state was highly significant in determining alternate conformations. When this position is empty, subsequent movement of Phe65 toward the space induces the closed form. On the other hand, while occupied, the overall conformation remains in the open form. This structural understanding should greatly assist structure-oriented drug design and enable control of the enzymatic activity.

show abstract

“…Structure-based drug design and metabolic considerations led to the development of additional non-nucleoside ADA inhibitors ( Fig. 4D) with oral bioavailability [327]. Molecular modeling simulations suggested that the imidazolecarboxamide and the hydroxyl group of this compound are at the same binding positions as the Ade and hydroxyl group of EHNA, while the 2,3-dichlorophenyl ring stabilizes the compound metabolically [327].…”

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

View full text Add to dashboard Cite

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

show abstract

Structure-Based Design and Synthesis of Non-Nucleoside, Potent, and Orally Bioavailable Adenosine Deaminase Inhibitors

Cited by 23 publications

References 25 publications

Structures of Substrate- and Inhibitor-Bound Adenosine Deaminase from a Human Malaria Parasite Show a Dramatic Conformational Change and Shed Light on Drug Selectivity

Structures of Substrate- and Inhibitor-Bound Adenosine Deaminase from a Human Malaria Parasite Show a Dramatic Conformational Change and Shed Light on Drug Selectivity

Structural Basis of Compound Recognition by Adenosine Deaminase

The Antiepileptic Potential of Nucleosides

Contact Info

Product

Resources

About