Hydration of Adamantane Skeleton: Water Assembling around Amantadine and Halo-substituted Adamantanes

Abstract

We performed Monte Carlo simulations to reveal the water distributions around adamantane derivatives. Adamantane derivatives attract water molecules, and specific water distributions are observed around the skeleton. Perfluoroadamantane attracts water more than adamantane.Adamantane (C 10 H 16 ) is a highly symmetric tricyclic aliphatic hydrocarbon that is the simplest of the diamondoids, with a dipole moment of 0 D. Adamantane is known as a valuable building block for polymers for the enhancement of their thermal stability or improvement of their physical properties.1,2 Adamantyl-bearing compounds are also used in the field of medicinal chemistry and drug development, and some of them are in clinical use.3 The adamantyl group is used to modify the water solubility and lipophilicity of an original compound that may be highly water soluble or poorly soluble. Through the incorporation of an adamantyl group into the structure, the membrane solubility can be changed to a value that may be clinically useful.The octanol/water partition coefficient, log P, 4 is used as an index of the lipophilicity of a compound and is often used to evaluate the bioavailability of candidate molecules for therapy. A positive value of log P indicates a preference of the compound for the lipid phase, and a negative value shows a preference for water. It is thought that a compound should have a reasonable value of log P to be a good candidate for a new drug. The log P value of adamantane is positive, yet lower than that of decane, which is also composed of ten carbon atoms.5 This feature affords adamantylbearing compounds with more tractable solubility properties compared to decane-substituted analogs, which may be much less soluble in water.3 Amantadine (1-aminoadamantane) is known as a blocker of the M2 channel activity of the influenza A virus, 6 and also as an antagonist against Parkinson's disease. 7 The estimated log P values of amantadine 5 and adamantane 3 are 2.22 and 4.24, respectively, indicating that the ratio of the water solubility to the lipophilicity of amantadine is roughly 100 times larger than that of adamantane.Although the water solubility of adamantane is very low, it is still slightly "soluble" in water, which is related to hydrophobic hydration.8 Previously, 9 we showed that the water molecules in the first solvent shell around adamantane are oriented in such a way that the dipole direction of water is tangential to the skeleton surface, and the hydrogen-bonding network is formed among the water molecules in the first shell as well as between the first shell and the outer shell.For the development of new drugs and materials utilizing adamantyl groups, it is necessary to estimate how attractive the adamantane skeleton is for water. To this end, we have performed Monte Carlo (MC) simulations of some adamantane derivatives surrounded by water molecules, and show how the water distribution changes by a substituent group.For the MC simulations, the molecular mechanics (MM) parameters of the solutes were created as follo...

Hydration Structure of Diamondoids from Reactive Force Fields

“…For instance, the molecules corresponding to the top and bottom edges of that map (α ≈ 0.5π, β ≈ ±1π) are aligned parallel to the AD surface, with only small variations, and the dipole directions are oriented tangential to the AD surface. The frequent occurrence of such oriented molecules is consistent with previous Monte Carlo and MD simulations that used non polarizable force fields. , According to these studies, the water molecules in the first hydration shell are tangential to the skeleton surface of the AD. However, this is the single only orientational mode reported.…”

“…This allowed us to shed new light on the electrostatic properties of the first hydration shell and its structure, which has been described as very unusual in experiments . We found a spectrum of water orientations, greatly expanding on what was known before in literature. , We showed that there are almost no interfacial C–H···O–H 2 bonds, in which we agree with experiments, except at very close distances to the interface, where they contribute to the stabilization of the water–water hydrogen bond network . However, we also showed that there is a substantial number of non-hydrogen bonded OH groups within the first hydration shell, which have also been observed around NDs and other hydrocarbons. ,− Generally, we found that for understanding hydrophobic hydration , it is of fundamental importance to know the effects of small surface perturbations on hydrophobic behavior.…”

Influence of Trimethylamine N-Oxide (TMAO) on the Three-dimensional Distribution and Alignment of Solvent Molecules in Aqueous Solution

“…The LennardJones parameters determined by Freindorf and Gao 15 were applied to the atoms of TMAO. The TIP3P water potential function 16 was employed for solvent molecules to compare the hydration pattern of TMAO with that of adamantane, 17 for which we had used TIP3P.…”

“…The number densities of O and H atoms of solvent water were calculated in the same way as in the previous work 17 (see Method S1). 12 The average dipole moment of solvent water at the position (x, y, z) was calculated, as follows:…”