Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

Cunha, Elaine F. F. da; Mancini, Daiana T.; Ramalho, Teodorico C.

doi:10.1007/s00044-011-9554-z

Cited by 25 publications

(7 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most stable conformation of the ligand inside the protein joining with the amino acid residues present in the active site (Val882, Thr827, and Lys800), which form hydrogen bonds with the ligand, was selected for 99 Tc and 13 C NMR calculations. This procedure was validated in previous studies . This study was carried out combining docking techniques and GIAO–DFT calculations at the QM interface for the NMR, using the same basis set and functional discussed before and the Gaussian 09 software…”

Section: Methodsmentioning

confidence: 99%

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

Mancini

Souza

Caetano

et al. 2014

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

The phenylbenzothiazole compounds show antitumor properties and are highly selective. In this paper, the (99)Tc chemical shifts based on the ((99m)Tc)(CO)3 (NNO) complex conjugated to the antitumor agent 2-(4'-aminophenyl)benzothiazole are reported. Thermal and solvent effects were studied computationally by quantum-chemical methods, using the density functional theory (DFT) (DFT level BPW91/aug-cc-pVTZ for the Tc and BPW91/IGLO-II for the other atoms) to compute the NMR parameters for the complex. We have calculated the (99)Tc NMR chemical shifts of the complex in gas phase and solution using different solvation models (polarizable continuum model and explicit solvation). To evaluate the thermal effect, molecular dynamics simulations were carried, using the atom-centered density matrix propagation method at the DFT level (BP86/LanL2dz). The results highlight that the (99)Tc NMR spectroscopy can be a promising technique for structural investigation of biomolecules, at the molecular level, in different environments.

show abstract

Section: Methodsmentioning

confidence: 99%

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

Mancini

Souza

Caetano

et al. 2014

Magnetic Reson in Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…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%

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Consequently, derived experimental data on the bioactive conformation should serve as verification wherever possible ( CUNHA et al, 2005). It should be kept in mind that the MD resulting structures can also be applied to construct the conformational ensemble profile (CEP) of each ligand into the active site, thus overcoming the scenario of a poor molecular conformational sampling (CUNHA et al, 2012;SODERO et al, 2012). Furthermore, crystallographic data of the enzyme-inhibitor complex can generate useful information about the enzyme-inhibitor interaction, as well as on the bioactive conformation of ligand in order to validate the chemical structures in 3D QSAR (CUNHA et al, 2013).…”

Section: Computational Molecular Modelsmentioning

confidence: 99%

Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

Freitas

Ramalho

2013

Ciênc. agrotec.

View full text Add to dashboard Cite

A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies) is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR) methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems.Index terms: Structural analysis, 2,4-dichlorophenoxyacetic acid, theoretical calculations. RESUMOUma prática comum para determinar a conformação de ligantes em compostos com vários graus de liberdade a serem utilizados em modelagem molecular (QSAR e estudos de ancoramento molecular) é realizar uma distribuição conformacional baseada em repetidas amostragens aleatórias, tais como o método Monte Carlo. Cálculos adicionais são frequentemente necessários. Esta rápida revisão descreve alguns métodos usados para análise conformacional e as implicações ao usarem algumas conformações selecionadas em QSAR. Um estudo de caso foi desenvolvido para o ácido 2,4-diclorofenóxi acético (2,4-D), um herbicida amplamente usado que se liga à enzima TIR1 ubiquitina ligase. O uso de tal aproximação e cálculos semi-empíricos não alcançou todos os mínimos possíveis para o 2,4-D. Além disso, as conformações e respectivas energias obtidas pelo método semi-empírico AM1 não concordam com as tendências calculadas em nível DFT. Resultados similares foram obtidos para o ânion carboxilato, que é a forma bioativa do 2,4-D. Finalmente, a estrutura cristalina e bioativa do 2,4-D não foi encontrada como um mínimo de energia usando MonteCarlo/AM1 e, de acordo com otimização em nível B3LYP/aug-cc-pVDZ, tem população similar ao outro confôrmero em solução aquosa implícita. Portanto, métodos para relação quantitativa entre estrutura e atividade (QSAR) baseados na estrutura química tridimensional não são fundamentais para fornecer modelos preditivos...

show abstract

Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

Cited by 25 publications

References 37 publications

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

Contact Info

Product

Resources

About

Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors

Cited by 25 publications

References 37 publications

99Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

99Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

Contact Info

Product

Resources

About

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex

⁹⁹Tc NMR as a promising technique for structural investigation of biomolecules: theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex