Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-<i>d</i>]pyrimidine Ring System. Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies

Settimo, Federico Da; Primofiore, Giampaolo; Motta, Concettina La; Taliani, Sabrina; Simorini, Francesca; Marini, Anna María; Mugnaini, Laura; Lavecchia, Antonio; Novellino, Ettore; Tuscano, Daniela; Martini, Claudia

doi:10.1021/jm050136d

Cited by 47 publications

(59 citation statements)

References 54 publications

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“…The structure of these drugs, including EHNA, resembles Ado, the endogenous substrate of the enzyme. Docking of EHNA to the ADA crystal structure revealed that the Ade NH 2 group formed a hydrogen bond with Asp 295 and 296, while the 2´-hydroxy group formed a hydrogen bond with the N hydrogen of His 17 and the S hydrogen of Cys 153 [326]. Modifications of the structure of EHNA using the 1-and 2-alkyl derivatives of the 4-aminopyrazolo [3,4-d]pyrimidine nucleus (Fig.…”

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

“…Modifications of the structure of EHNA using the 1-and 2-alkyl derivatives of the 4-aminopyrazolo [3,4-d]pyrimidine nucleus (Fig. 4C) also led to potent inhibitors of ADA [326]. Structure-based drug design and metabolic considerations led to the development of additional non-nucleoside ADA inhibitors ( Fig.…”

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

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The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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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.

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Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

Section: Recently Developed Drugs Acting On the Adenosinergic System mentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…The set of KIEs for the three ADAs were determined under competitive conditions. The intrinsic [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] N], [6-13 C], and [6- 30 Adenylate kinase (AK), pyruvate kinase (PK), hexokinase, and bovine spleen adenosine deaminase (BtADA) were purchased from Sigma. Phospho-D-ribosyl-1-pyrophosphate (PRPP) synthase and adenine phosphoribosyltransferase (APRTase) were purified according to the methods reported previously.…”

Section: Introductionmentioning

confidence: 99%

Transition-State Variation in Human, Bovine, and Plasmodium falciparum Adenosine Deaminases

2007

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Adenosine deaminases (ADAs) from human, bovine and Plasmodium falciparum sources were analyzed by kinetic isotope effects (KIEs) and shown to have distinct but related transition states. Human adenosine deaminase (HsADA) is present in most mammalian cells and is involved in Band T-cell development. The ADA from Plasmodium falciparum (PfADA) is essential in this purine auxotroph and its inhibition is expected to have therapeutic effects for malaria. Therefore ADA is of continuing interest for inhibitor design. where N1 protonation is partial and the bond order to the attacking hydroxyl nucleophile is nearly complete. The key structural variation among PfADA, HsADA and BtADA transition states lies in the degree of N1 protonation with the decreased bond lengths of 1.92 Å, 1.55 Å and 1.28 Å, respectively. Thus, PfADA has the earliest and BtADA has most developed transition state. This conclusion is consistent with the 20 to 36-fold increase of k cat in comparing PfADA with HsADA and BtADA.

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“…However, recent progress has been reported by Terasaka et al and by some of us who have developed a new generation of nonnucleoside ADA inhibitors (II, III, and IV in Fig. S1) (6)(7)(8)(9)(10)(11). Unfortunately, the understanding at molecular level of the ligand/ADA interaction is hampered by the pronounced ability of the active site to accommodate different inhibitors and by the crucial role played by water molecules during ligand binding.…”

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confidence: 99%

Sampling protein motion and solvent effect during ligand binding

Limongelli

Marinelli

Cosconati³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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110

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An exhaustive description of the molecular recognition mechanism between a ligand and its biological target is of great value because it provides the opportunity for an exogenous control of the related process. Very often this aim can be pursued using high resolution structures of the complex in combination with inexpensive computational protocols such as docking algorithms. Unfortunately, in many other cases a number of factors, like protein flexibility or solvent effects, increase the degree of complexity of ligand/protein interaction and these standard techniques are no longer sufficient to describe the binding event. We have experienced and tested these limits in the present study in which we have developed and revealed the mechanism of binding of a new series of potent inhibitors of Adenosine Deaminase. We have first performed a large number of docking calculations, which unfortunately failed to yield reliable results due to the dynamical character of the enzyme and the complex role of the solvent. Thus, we have stepped up the computational strategy using a protocol based on metadynamics. Our approach has allowed dealing with protein motion and solvation during ligand binding and finally identifying the lowest energy binding modes of the most potent compound of the series, 4-decyl-pyrazolo[1,5-a]pyrimidin-7-one.ADA | well-tempered metadynamics | ligand/protein docking | path collective variables | reweighting algorithm A denosine Deaminase (ADA) regulates the purine metabolism by catalyzing the irreversible hydrolysis of adenosine to inosine and 2′-deoxyadenosine to 2′-deoxyinosine. Thus, this enzyme plays a crucial role in many pathologies such as inflammation, some types of cancer, and others which are strictly connected to the physiological level of these nucleosides (1-5). Despite great efforts in developing ADA inhibitors, only Pentostatin is currently in clinical use (I in Fig. S1) (3). However, recent progress has been reported by Terasaka et al. and by some of us who have developed a new generation of nonnucleoside ADA inhibitors (II, III, and IV in Fig. S1) (6-11). Unfortunately, the understanding at molecular level of the ligand/ADA interaction is hampered by the pronounced ability of the active site to accommodate different inhibitors and by the crucial role played by water molecules during ligand binding. A rational drug design is further complicated by the fact that in response to different inhibitors, ADA can assume either an open or a closed conformation by changing the position of the H3 α-helix (Thr57-Ala73). The open conformation corresponds to the apo-form (PDB ID code 3iar) and is preferred when a nonnucleoside inhibitor is bound (12, 13). In this case, the active site presents a hydrophilic subsite S0 and three hydrophobic subsites F0, F1, and F2 (Fig. 1A) (13). The S0 subsite is defined by the structural gate formed by a β-strand (Leu182-Asp185) and two leucine side chains attached to the H3 α-helix while the F0 site is formed by the hydrophobic side chains of the H3 α-helix. In the op...

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Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-d]pyrimidine Ring System. Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies

Cited by 47 publications

References 54 publications

The Antiepileptic Potential of Nucleosides

The Antiepileptic Potential of Nucleosides

Transition-State Variation in Human, Bovine, and Plasmodium falciparum Adenosine Deaminases

Sampling protein motion and solvent effect during ligand binding

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