4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors

Matulenko, Mark A.; Paight, Ernest S.; Frey, Robin R.; Gomtsyan, Arthur; DiDomenico, Stanley; Jiang, Meiqun; Lee, Chih‐Hung; Stewart, Andrew O.; H, Yu; Kohlhaas, Kathy L.; Alexander, Karen M.; McGaraughty, Steve; Mikusa, Joseph P.; Marsh, Kennan C.; Muchmore, Steven W.; Jakob, Clarissa L.; Kowaluk, Elizabeth A.; Jarvis, Michael F.; Bhagwat, Shripad S.

doi:10.1016/j.bmc.2006.12.029

Cited by 27 publications

(24 citation statements)

References 53 publications

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“…Adenosine kinase inhibitors (organic compounds and natural inhibitors) reported in the literature were generated by ChemSketch [14–18]. The generated structures were subjected to DS 2.5 for ligand minimization.…”

Section: Methodsmentioning

confidence: 99%

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Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

Kar

Ansari

Suryadevara

et al. 2013

BioMed Research International

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Enzyme adenosine kinase is responsible for phosphorylation of adenosine to AMP and is crucial for parasites which are purine auxotrophs. The present study describes development of robust homology model of Leishmania donovani adenosine kinase to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Docking calculation using reported organic small molecules and natural products revealed key active site residues such as Arg131 and Asp16 for ligand binding, which is consistent with previous studies. Molecular dynamics simulation of ligand protein complex revealed the importance of hydrogen bonding with active site residues and solvent molecules, which may be crucial for successful development of drug candidates. Precise role of Phe168 residue in the active site was elucidated in this report that provided stability to ligand-protein complex via aromatic-π contacts. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development.

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Section: Methodsmentioning

confidence: 99%

“…In this report we have prepared a molecular dataset using the reported adenosine kinase (Adk) inhibitors [14–18] and natural products from Nigerian medicinal plants [17]. Since the crystal structure of Ld Adk is not reported till date, we proceed with homology modeling.…”

Section: Introductionmentioning

confidence: 99%

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

Kar

Ansari

Suryadevara

et al. 2013

BioMed Research International

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“…Further structure-activity studies established that the 4-amino pyrimidine fragment and the aryl ring in the C(7) position are crucial pharmacophoric elements for pyridopyrimidines. However, although substances with higher in vitro potency have been produced, their in vivo efficacy remained suboptimal [323]. Coformycin and 2´-deoxycoformycin are outstandingly potent inhibitors of ADA.…”

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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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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“…ADO was taken out, hydrogens were added and correct protonation states were assigned and the protein was then minimized using CHARMM force field. To represent the open binding site of protein, a second conformation of human AK (PDB code 2I6B), complexed with an alkynylpyrimidine inhibitor [26], was prepared using the similar procedure as above without considering the waters.…”

Section: Preparation Of Proteins and Ligandsmentioning

confidence: 99%

Deciphering ligand dependent degree of binding site closure and its implication in inhibitor design: A modeling study on human adenosine kinase

Bhutoria¹,

Ghoshal²

2010

Journal of Molecular Graphics and Modelling

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4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors

Cited by 27 publications

References 53 publications

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

The Antiepileptic Potential of Nucleosides

Deciphering ligand dependent degree of binding site closure and its implication in inhibitor design: A modeling study on human adenosine kinase

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