Enthalpy-entropy compensation and water networks

Enthalpy-entropy compensation (EEC) is an endlessly interesting phenomenon; it's the kind of topic that makes scientists either roll up their sleeves for a good fight or slowly walk away from the table. The basic idea is simple; when you are building new chemical functionality into a drug molecule to interact better with a protein (improving ∆H) you are also tying down the molecule (worsening ∆S) and constraining its movement. However since the two variables oppose each other this won't be reflected in the overall ∆G of binding which will stay the same.

Scientists have been going back and forth over the causes of EEC and now there's a new paper from George Whitesides's group at Harvard, Schrodinger and Brookhaven which sheds some light on one possible, usually neglected factor: the subtle changes in the thermodynamics of the network of water molecules surrounding a ligand. These are not the water molecules displaced by the ligand from the protein pocket (which have received considerable attention over the last decade or so) but the ones on the surface that contact the ligand on the outside.

The paper is based on a workhorse protein system that Whitesides's group has been working on for a while now - carbonic anhydrase. The protein is stable, relatively rigid, biochemically well-studied, amply expressed and easily crystallized by itself and with several ligands; all features which make it a good model system to look at the thermodynamics of binding. Whitesides's group has found out that you can have ligands with different fluorination patterns that bind to the protein and show very similar ∆Gs of binding. This is unexpected, since you expect additional fluorines to give you better entropy from the hydrophobic effect.

To explore the phenomenon the authors use two techniques; x-ray crystallography and molecular dynamics simulations. The former provides information on intermolecular interactions while the latter provides information on the thermodynamics of surrounding water molecules, more specifically about their enthalpy and entropy. The MD and thermodynamic calculations are done using the WaterMap tool from Schrodinger.

From the crystal structures the authors find that the enthalpy of binding can actually get unfavorable from the added fluorines as a result of repulsive interactions with a few oxygens in the protein. Since ∆G stays the same this means that the unfavorable ∆H in the active site might be compensated for by ∆H changes in the water network surrounding the ligand along with corresponding ∆S adjustments. In the picture above, water molecules with more favorable ∆H values are colored green while the unfavorable ones are colored red. 

Notice the difference between the three difluorinated analogs: the 4,6 analog has the most green waters, the 5,6 analog has the most red waters (and an extra red water compared to the others) and the 6,7 analog is somewhere in between. The gradation of unfavorable water molecules around the three compounds tracks well with enthalpies extracted from ITC. The entropies duly compensate. The thermodynamics of surface water molecules therefore certainly seem to be one possible reason for the EEC. It's also worth noting that the behavior of the water molecules corresponds to what you would call an "enthalpy-driven hydrophobic effect".

While we are neglecting second-order effects and while it's still hard to get quantitative agreement down to a kcal or so, I like the fact that we can eyeball such figures and at least qualitatively rank cases by favorable and unfavorable enthalpies. I also find it promising that we can actually do this kind of thing for surface water molecules which are part of a network; ten years ago most people might have thrown up their hands when asked to do this. Of course not every drug-protein binding case is going to be dictated by surface water behavior but the fact that we can at least get a semi-quantitative look at this important factor is, in my opinion, a valuable stepping stone toward the future.

Reference: 

Water wires and hydrophobics

Quick survey of two interesting articles

P. Balaram's group at the Indian Institute of Science in Bangalore has turned a serendipitous observation into a nice study of a single file water wire inside a hydrophobic peptide nanotube. Based on the crystallographic data two models have been proposed for this wire. Such a structure can be the starting point for interesting MD simulations.
DOI: 10.1021/ja9038906

A group at Boston University and SLAC has found an explanation for the catalytic action of acetoacetate decarboxylase that refutes an elegant explanation provided by the famous late bioorganic chemist Frank Westheimer. Westheimer had proposed that a key lysine involved in nucleophilic attack was neutral because of proximity to another lysine; the electrostatic repulsion between two charged lysines would not favor the ionized state for both of them. The present group has obtained the crystal structure for the enzyme and finds that the two lysines are in fact far apart. Thus, electrostatic repulsion could not be responsible for the neutral nature of the lysine. Instead, using an elegant set of experiments, they find that it's being in a hydrophobic cavity that favors the lack of ionization.
doi:10.1038/nature07938

Water-Inclusive Docking with Remarkable Approximations

The role of water in mediating protein-ligand interactions has now been well-recognized by both experimentalists and modelers. However it's been relatively recently that modelers have actually started taking the unique roles that water plays into account. While the role of water in bridging ligand and protein atoms is obvious, a more subtle but crucial role of water is to fill up hydrophobic pockets in proteins. Such waters can be very unhappy in such pockets because of both unfavourable entropy (not much movement) and enthalpy (inability to form a full complement of 4 hydrogen bonds). If one can design a ligand that will displace such waters, significant gains in affinity would be obtained. One docking approach that does take such properties of waters into consideration is Schrodinger's Glide, with a recent paper attesting to the importance of such a method for Factor Xa inhibitors.

Clearly the exclusion of water molecules during docking and virtual screening (VS) will hamper enrichment factors, namely how well you can rank actives above inactives. Now a series of experiments from Brian Shoichet's group illustrates the benefits of including waters in active sites when doing virtual screening. These experiments seem to work in spite of two approximations that should have posed significant problems, but surprisingly did not.

To initiate the experiments, the authors chose a set of 24 targets and their corresponding ligands from their well-known DUD ligand set. This is a VS data set in which ligands are distinguished by topology but not by physical properties such as size and lipophilicity. This feature makes sure that ligands aren't trivially distinguished by VS methods on the basis of such properties alone. Importantly, the complexes were chosen so that the waters in them are bridging waters with at least two hydrogen bonds to the protein, and not waters which simply occupy hydrophobic pockets. Note that this would exclude a lot of important cases where affinity comes from displacement of such waters.

Now for the approximations. Firstly, the authors treated each water molecule separately in multiple configurations. They then scored the docked ligands against each such configuration as well as the rest of the protein. The waters were treated as either "on" or "off", that is, either displaced or not displaced. Whether to keep a water or not depended on whether the score improved or not when it was displaced by a ligand. The best scored ligands were then selected and figured high on the enrichment curve. This is a significant approximation because the assumption here is that every water contributes to ligand binding affinity independently of the other waters. While this would be true in certain cases, there is no reason to assume that it would generally hold.

The second approximation was even more important and startling. All the waters were regarded as energetically equivalent. From our knowledge of protein-ligand interactions, we know that the reason why evaluating waters in protein active sites is such a tricky business is precisely because each water has a different energetic profile. In fact the Factor Xa study cited above takes this profile into consideration. Without such an analysis it would be difficult to tell the medicinal chemist which part of the molecule to modify to get the best binding affinity from water displacement.

The most important benefit of this approximate approach was a linear increase in computational time instead of an exponential one. This was clearly because of the separate-water configuration approximation. The calculation of individual water free energies would also have added to this time.

In spite of these crucial approximations, the results indicate that the ability to distinguish actives from inactives was considerably improved for 12 out of 24 targets. This is not saying much, but even 50% sounds like a lot in the face of such approximations. Clearly an examination of the protein active site will also help to evaluate which cases will benefit, but it will also naturally depend on the structure of the ligand.

For now, this is an encouraging result and indicates that this approach could be implemented in virtual screening. There are probably very few cases where docking accuracy decreases when waters are included. With the sparse increases in computational time, this would be a quick and dirty but viable approach for virtual screening.

Reference:
Niu Huang, Brian K. Shoichet (2008). Exploiting Ordered Waters in Molecular Docking Journal of Medicinal Chemistry, 51 (16), 4862-4865 DOI: 10.1021/jm8006239

Water and Amyloid Self-Assembly

One of the most significant, interesting and yet poorly understood effect in chemistry and biology is the hydrophobic effect. An important manifestation of its role in biology is invoked by the picture of two parallel hydrophobic plates with water between them that are slowly brought close to each other. At a certain distance called the 'dewetting distance', dewetting is observed and the water suddenly gets expelled out from them. Since nature abhors the resulting vacuum, the two hydrophobic surfaces collapse and 'stick' to each other.

Bruce Berne and his colleagues at Columbia had hypothesized that such dewetting could be observed in biological systems. A remarkable dewetting transition in the protein mellitin and in other proteins in the PDB provided evidence. Now they and others investigate such possible roles of water in the formation of amyloid by molecular dynamics simulations. They focus on the central core peptide of the Alzheimer's Aß (1-42) peptide consisting of the 16-22 region. Since one of my projects involves investigation of the self-assembly of this segment, it is of particular interest to me. This oligopeptide is interesting because it seemingly is the smallest stretch of the bigger parent that also forms the characteristic cross-beta sheet structure of amyloid. Importantly, it is also soluble which means it is more amenable to structural characterization compared to the bigger peptide.

Berne's group investigates the role that water plays between two sheets of 16-22 consisting of nine peptides each. The MD simulations were run for 1 ns, a typical time for such systems. The dewetting critical distance was found to be 12.8 A. Compare this with the classic repeat distance between amyloid beta-sheets which is 9.9 A. Basically two types of phenomena were observed depending on different trajectories and conditions; dewetting, which means that water expulsion was followed by hydrophobic 'collapse', and the simultaneous occurence of expulsion and collapse. The latter phenomena can be interpreted as a kind of 'lubrication' effect that water has been hypothesized to play in the folding of proteins. They haven't been able to put a finger on which is the phenomenon in the 'real' system, but it at least seems plausible that dewetting could be observed in such systems. In the cases where dewetting is not the driving force for assembly, they dissect the interaction energies of different amino acid residues that contribute to the total energy, and find that the Phe-Phe energy contributes to the most.

From a methodological standpoint, the investigation is complicated by the fact that, as in other such studies, the results seem to depend on the methods used. This is a common characteristic of modeling and theoretical investigations. In this case, turning off the protein-water Van der Waals forces causes dewetting in every instant, perhaps not a surprising conclusion since there is now no attraction at all between the water and protein. Also, turning off the electrostatic forces caused no changes, which means that electrostatic attraction plays a small role in the system. Again probably not too surprising. A third observation is that the choice between the two phenomena depends on rather small changes in temperature.

The interpretations are also rendered ambiguous by the fact that amyloid surfaces and indeed most 'hydrophobic' protein surfaces are a poor approximation to two parallel hydrophobic plates. It should be noted that the attractive energy of interaction between two flat plates separated by a distance R is inversely proportional to the square of R. Compare this with the case of two spheres of radius R whose classical Van der Waals attractive energy is proportional to the sixth power of R. That means that in the case of the plates the attraction falls off much more slowly which can lead to significant dispersion forces even at relatively long separation.

This paper, while not leading to very novel or practical results, sheds light through detailed investigation of the possible role water can play between amyloid sheets. It again demonstrates the important effect that choice of methods and parameters can have on observations.

Krone, M.G., Hua, L., Soto, P., Zhou, R., Berne, B.J., Shea, J. (2008). Role of Water in Mediating the Assembly of Alzheimer Amyloid Aß (16-22) Protofilaments. Journal of the American Chemical Society, 130(33), 11066-11072. DOI: 10.1021/ja8017303

Why is body temperature 36 degrees celsius?

While I was doing an unrelated search on the Nature website, I came across this intriguing debate about why body temperature is maintained around 36 degrees and not some other value. (Nature, Vol 324, December 4, 1986, p. 418)

The discussion was initiated by a letter from John Paul, a scientist in Australia who contended that the specific heat capacity of water is lowest at 36 degrees, and therefore heat loss would be minimal at that temperature

But he neglected a fundamental principle of physical chemistry; the rate of heat loss is proportional to the difference between the temperature of the body and that of the surroundings and is independent of the specific heat capacity (remember high school and Newton's Law of Cooling?). More importantly, the specific heat capacity of a body can be thought of as a measure of how well the body offers "resistance" to fluctuations in temperature. The reason why water works so well as an essential life fluid for example is because its specific heat is so high; there is minimal fluctuation in the temperature of water when heat is injected or taken away from it.

Thus, an optimal substance for maintaining a given temperature would be one whose specific heat capacity is as high as possible under the given circumstances, not one whose specific heat capacity is minimum at the given temperature.

These facts were pointed out by William Calder from the University of Arizona and by Steven Benner and Jack Dunitz at the ETH, Zurich. Dunitz as is known is an extremely versatile scientist, a veteran researcher and one of the greatest structural chemists and technical writers of the last century.

Dunitz and Benner make their objections to Paul's explanation clear and offer an alternative partial explanation; that 36 degrees is the optimum compromise between viscosity and hydrophobicity. It's high enough for the viscosity to not become so low as to impede diffusion-limited processes, and low enough that hydrophobic molecules do not "dissolve" too easily.

Natural selection must have taken a remarkable number of factors into account in optimizing this property.

Life's Matrix

Philip Ball's excellent new Chem. Rev. review on water and its importance in the chemistry of life.

Water-inhibitor synergy in CDKs

An interesting paper published in the J. Chem. Inf. Mod. investigates the role of water molecules in CDK2 and CDK5 active sites. The authors use MD simulations to simulate water and inhibitors (in this case the well-known indirubin analogs) in the active site of the CDKs. The interesting observation they make is that in some cases, the inhibitor "recruits" a water molecule to form a bridged interaction with an atom in the protein, thus achieving the "correct" binding mode. In other cases, blockage of the active site by a loop prevents this water grabbing trick.

The study also highlights how it can make a big difference between using monomeric CDK and CDK bound to a cyclin when simulating nib ("nib": inhibitor...apparently new yippie slang) binding. In this case, the difference is in the water recruitment.

Again, one is reminded of the many subtle factors, including water interactions, that dictate differences between nib binding to different but similar kinases.

Slippery questions

Here are a few questions about water that I have either read, or which recurringly occured to me through reading about the stuff that life's made from. Some of them are easy to answer, some are difficult. Some are general questions, others are subsets of these general questions. Most of them are connected. Many are of the "simple-yet-extremely-tricky-to-answer" kind. I know the answer to some of the questions, don't know those to others, and am not sure about yet other ones.

1. What is the strength of an average hydrogen bond in bulk water?
2. What is the strength of an average hydrogen bond in "biological water" (solvating proteins for example) and the strength of a hydrogen bond in the first hydration shell?
3. What is the lifetime of an average hydrogen bond in bulk water? In biological water?
4. Is hydrogen bond exchange between water a discrete phenomenon or a concerted one?
5. How many hydrogen bonds on an average does a water molecule form in bulk? In confinement? In biological water?
6. Is there a long-range "hydrophobic bond"?
7. Can one always predict de novo whether displacement of a water molecule from a hydrophobic pocket of a protein by a ligand will lead to greater binding affinity? How?
8. How does enthalpy-entropy compensation work in case of water?
9. What is the difference between hydration dynamics of bulk water and biological water?
10. What is the exact difference between hydrogen bonding structure and dynamics in ice and liquid water?
11. How does the molecular structure and hydrogen bond network of liquid water change according to the temperature? What is the difference between these properties for bulk water at room temperature and at 4 degrees celsius (at maximum density)? For biological water? Corollary of this question: what changes does the molecule structure of water undergo at low temperatures in biological systems and around biomolecules?
12. How do we explain the Hofmeister effect- the differential ability of various ions to precipitate proteins?
13. How does the hydrophobic effect depend on size of solute? On conformation?
14. Can we develop a comprehensive first principles water model?

More to come as I think about this. Some of these questions have been addressed before at the Water in Biology blog.

Can water stand the heat of a hydrophobic carbon nanotube?

"If you cannot stand the lipophilia, get out of the nanotube"- Anon

Yes. And this sort of ties in with the recent discussions of water in hydrophobic channels and cavities that I have been reading , discussions that can have a direct impact on ligand design (and also "rational" drug design). At least in once case, a simulation of water inside a carbon nanotube, the authors find that water does indeed get inside this greasy den. This study if part of many recent studies which I believe challenge our basic notions of "hydrophobicity" of surfaces and cavities.

I was not aware of this CNT paper, which was published in Nature in 2001 (Nature | Vol 414 | 8 November 2001 | pg. 188-190). The paper involved simulating water around a CNT. The researchers found that a few water molecules do enter the CNT in single file and exit, as the CNT is wide enough to accomodate only the diameter of a water. The interesting explanation for why the waters can ever get inside such an unwelcome environment is given by the energetics; apparently the waters can form two hydrogen bonds inside the nanotube, but fluctuations in the number of hydrogen bonds even in bulk means that they are incompletely hydrogen bonded even in bulk. Part of the explanation also may be that the Hbonds inside the tube have better geometrical characteristics, although I am not sure how much enthalpic advantage such slight changes in geometry provide to a Hbond.

This is a very significant fact in my opinion, and does not completely tie in with the study of Friesner et al. where they say that expelling a water molecule from a protein cavity into bulk may be enthalpically favourable because in bulk water is assumed to form its full complement of hydrogen bonds. I think the verdict may be still out there, as far as the enthalpic gain of waters expelled from hydrophobic protein active sites is concerned. On the other hand, in the nanotube study, it's clear that since the waters are certainly entropically constrained inside the tube, which means that the enthalpic advantage is what drives them in, even if they don't stay there forever.

However, the flags which are always raised in my mind when I read such a study pertain to the method dependence of the results. After all, any model is as good as the parameters in it. For example, the very reason why people do simulations of water under confinement is because they cannot study it by experiment, but at the same time, they are using bulk or gas phase parameters to represent the water molecules. In this study, the authors use Bill Jorgensen's TIP3P water model, which is a very good model that nonetheless represents bulk and gas-phase properties. The fact that the simulation results depend on model parametrization becomes clear when the authors change the depth of the energy well of the Lennard-Jones potential by a mere 0.05 kcal/mol, they observe a drastic change in the wetting event, with a two-step wetting-dewetting transition in a a nanosecond. The question arises is; what if they had used another value for the well depth? Would they have then observed no wetting at all? And would this then have been a representation of the real world? As usual, the question here is of the transferability of parameters, in this case whether the parameters from bulk apply under confinement. Unless there is a better hypothesis and reason, there may be some good reason to believe this transferability, but as usual, with what confidence does the model represent the "real world" is another question.

On a related note, is anyone aware of studies in which such confined-water parameters have been experimentally obtained?

How much water does it hold?

The last couple of days, in connection with the behaviour of water in protein active sites, I have been reading about water and the hydrophobic effect in general, and I found it fascinating how little we really know about both of these in general. For one thing, we still seem to have miles to go in understanding ice, bulk water, and the transition between the two. There was a debate between Richard Saykally of Cal Berkeley and Anders Nilsson of Stanford about the number of hydrogen bonds that a water molecule makes in bulk water. One would think that something as simple as this would have been unraveled by now. But nothing about water is simple. Nilsson published the pretty amazing contention that many water molecules in bulk liquid water at room temperature form only two hydrogen bonds. This would mean that those hydrogen bonds are unusually strong. This paper sparked heated debate, and Saykally was a vocal opponent, countering with his own experiments, and contending that it would be a walk across the street to Stockholm if Nilsson's viewpoint turned out to be true. I am no water expert, but the best value for the energy of an average hydrogen bond in bulk water that I have come across seems to be 1.5 kcal/mol (determined by Saykally), which can definitely be less than that in a protein active site. At least for now, this discussion of "average" hydrogen bonds generally sounds a little slippery to me.

I think that this whole issue of how much a hydrogen bond in bulk water is worth could affect how much gain in energy a water molecule displaced from a protein active site might gain. Friesner et al. in their recent publications indicate that water molecules which cannot form their full complement of hydrogen bonds in a protein active site because of confinement could get an enthalpic advantage if they are pushed out into solvent. I think there's much less ambiguity about the entropic advantage that such a water molecule could have. Then there's also Dunitz's whole argument about entropy-enthalpy compenstation (see previous post) which could factor in...I am still really groping about for coherence in this landscape.

As far as hydrophobic interactions are concerned, while the general idea that the hydrophobic effect is entropically driven seems correct, it also seems situation dependent, especially varying with the temperature. One of those basic important things to note is that the enthalpy of transfer for a nonpolar solute to water is close to zero, and can even be slightly favourable. But when two nonpolar surfaces in water aggregate, it's the entropy of disordering waters clustered around the solute that is very favourable. As usual, even these seemingly simple issues are draped in subtleties. Among others, Themis Lazaridis has explored this very interestingly in a review (2001), in which he cements the "classical" view of the hydrophobic effect. He also counters arguments about the similar energy of cavity creation in water compared to some other solvents by saying that while this may be true, the decomposition of factors contributing to the energy might be different for the two cases.

And finally, and I should have posted about this a long time back, Water In Biology, a great blog all about the molecular intricacies of water, from Philip Ball, staff writer for Nature and author of many excellent books, including H2O: A biography of water.

Water really seems like a testament to that quote by T.S. Eliot about coming back to the beginning again and again, and newly getting to know a place every time. There are just so many things about it we don't understand.

Nature adores a vacuum?

Well, ok, nature does not actually adore a vacuum, but what are we then to make of Bruce Berne's newest PNAS piece, in which he talks about water molecules in protein active sites that are so horribly unhappy that they would almost let a vacuum take their place?

The article comes on the heels of Friesner et al.'s comprehensive JMC 06 Glide XP article, which was an impressively comprehensive instance of how computational chemists can take into consideration the detailed physical chemistry of protein-ligand/drug interactions. As usual, electrostatics, van der Waals interactions, and desolvation among other things are taken care of. As usual, it turns out that in most earlier studies, the 'other half'-water-had not been considered. No wonder attempts to explain diabolically strong interactions like that of streptavidin-biotin (the strongest protein-ligand interaction known) resulted in drastic underestimates of the binding energy. With their latest framework, Berne et al. seek to remedy this situation. They make a couple of elementary sounding but oft neglected and important points:

1. Water is not going to be happy in a place in a protein where it is surrounded by a hydrophobic enclosure.

2. It is not going to be happy if it cannot make its full complement of hydrogen bonds with the protein/with other water molecules.

3. Even if it can make such bonds, it is not going to be happy if there are only one or two configurations in which it can do so.

4. Clearly, such water molecules are going to be more than happy to be kicked out by ligand atoms which can form their full complement of h-bonds with protein residues. These bonds, if they form part of a ring or if they are in close vicinity, have been called correlated hydrogen bonds. As per the authors' interpretation, its is these correlated hydrogen bonds that give special binding stability to examples like the streptavidin-biotin complex.

Obviously, like all life forms, water aspires to that highest ideal- freedom.

In the PNAS article, Berne et al. examine three cases, including streptavidin and COX 2 binding, in which water seems to be simply aching to get of the protein cavity. In the case of streptavidin, five water molecules form a metastable ring as depicted above. They do manage to form bonds with each other and with protein residues, but they are hopelessly trapped on top and bottom by hydrophobic parts. In this case, as explained in the JMC piece, the atom-atom pairwise addition principle does not work for hydrophobic enclosures. Clearly, the sum of the parts is not equal to the whole here, and the effect of two hydrophobic atoms, one each on top and bottom, is different from the calculated pairwise sum of effects for two atoms .

The word "metastable" is the best word I can think of for describing this unhappy situation for water. Surreal, simmering, patient, but waiting to become free.

In the case of COX 2, I saw a few statements which neither me nor my advisor could make sense of at first. Aristotle notwithstanding, it seems that there are actually some solvation situations which are almost as bad as a vacuum. Or even worse? Consider what the authors have to say:

The Cox-2 active site was found to contain no persistent hydration sites and is in fact entirely devoid of solvent in 80% of the simulation, despite the cavity sterically accommodating approximately seven water molecules. The high excess chemical potential of the binding-cavity solvent is due to an inability of the water molecules to make hydrogen bonds with the surrounding hydrophobic protein residues and other water molecules...An extreme case of hydrophobic enclosure is observed in the Cox-2 binding cavity, where no energetically stable solvent configurations appear to exist; insertion of ligand hydrophobic groups into such a region of persistent vacuum will result in substantially larger free-energy liberation than would be expected if the binding cavity were treated as solvated.

Well...I second the study; water, that humble but amazingly complex liquid, has often been neglected and underestimated in studies of protein-drug-ligand interactions.

Almost concomitantly, Essex et al. have published a report in JACS, in which they examined the nature of water molecules in active sites. They find that most of the water molecules are displaceable. Not surprisingly, they conclude that the binding affinity of the ligand depends upon the nature and environment of the water molecules. It's a good statistical study.

A central point that is coming to light through such studies is that the absolute hydrophobicity/hydrophilicity of a ligand certainly does not constitute the whole story. This may well be kept in mind by medicinal chemists who aim at modulating these properties of drug-like molecules from SAR studies. Sometimes, a single well-positioned ligand atom which displaces one or two extremely metastable water molecules can lead to orders of magnitude of binding affinity, which cannot be predicted from absolute characteristics of the ligand.

As usual, quality, not quantity, matters.

Addendum:
Another nice 3 page review I found in the rarely read Chemical Biology and Drug Design again makes the case. The review explores the thermodynamic aspects of drug-protein binding, and says among other things:

As the major contributors to the binding enthalpy are polar groups, a common misconception is that enthalpically driven compounds must be highly polar and that consequently their bioavailability will be compromised. In fact, what is often observed experimentally is that compounds with the same number of polar groups have vastly different binding enthalpies...To generate a favorable binding enthalpy, it is not the number of polar groups that matters but the quality of their interactions with the target. It is better to have few groups that establish strong interactions than a large number of groups mostly paying the desolvation penalty.

Again, by a "few groups", all that is needed is two functional groups that can kick out a metastable water molecule, and your job might be done.