Abstract
The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs. Understanding the behavior of these molecules in solution and predicting their ability to self-assemble will accelerate new discoveries. We propose a computational approach based on density functional theory, a polarizable continuum solvation description of the aqueous environment, and an efficient search procedure to probe the potential energy surface, to determine the structure and thermodynamic stability of molecular clusters of adenosine analogues in solution, using caffeine as a model. The method was validated as a tool for the prediction of the impact of small structural variations on self-assembly using paraxanthine. The computational results were supported by isothermal titration calorimetry experiments. The thermodynamic parameters enabled the quantification of the actual percentage of dimer present in solution as a function of concentration. The data suggest that both caffeine and paraxanthine are present at concentrations comparable to the ones found in biological samples.
Highlights
The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs
The self-association of caffeine has been studied experimentally using a variety of techniques including NMR23–25 and FTIR spectroscopies,[26] dynamic light scattering (DLS),[27,28] osmometry,[29] fluorescence,[30] thermal analysis and differential scanning calorimetry (DSC).[31,32]
We present a quantum mechanical continuum solvation approach as a computational tool that allows prediction of the behaviour in solution of adenosine-analogues (AA) by determining the structure and thermodynamic stability of their molecular clusters (AA)n (n = 2–4), in solution, at concentrations comparable to the ones found in biological samples
Summary
The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs. Caffeine used in combination with melatonin was shown to have antiamyloidogenic action, for the treatment of neurodegenerative diseases.[21] Borota et al have demonstrated recently that caffeine enhances consolidation of long-term memory in humans.[22] There is considerable interest in understanding the mechanism by which caffeine and more generally adenosine analogues can interact with different receptors, as this may subsequently lead to the identification of new compounds with drug-like activity In this context, information on a new molecule’s behaviour in solution and its potential for self-assembly, its degree of complexation (i.e. dimers, trimers and tetramers) and the relative distribution, is a key requirement. These simulations were, conducted at the limit of solubility of caffeine in water (about 16 mg mLÀ1) which is approximately five orders of magnitude higher than the concentration range at which caffeine is present in biological systems (0.002 mg mLÀ1 in plasma).[36,37,38] Such low concentrations would require simulation at the limit of MD techniques, containing hundreds of millions of solvent molecules
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