06 December 2011

Are enthalpic binders more selective than entropic binders?

Thermodynamics is one of those abstract subjects that can have surprising real-world implications. The two components of free energy, enthalpy and entropy, are simplistically associated in drug discovery with polar interactions for the former and hydrophobic interactions for the later. Some researchers have suggested that enthalpically-driven binders are better starting points for optimization, and that best-in-class drugs rely more on enthalpy than entropy. In a recent paper in Drug Discovery Today, Yuko Kawasaki and Ernesto Freire at Johns Hopkins University suggest that enthalpic binders may also be more selective.

Medicinal chemists apply two general strategies to improve selectivity: increase the affinity of a compound for its target more than for off-targets, or decrease the affinity of a compound for off-targets. Kawasaki and Freire argue that the first is more likely to result from entropic interactions, while the second is more likely to result from enthalpic interactions. This is because nonpolar (entropic) interactions are often tolerant of mismatches; a hydrophobic substituent might improve the affinity of your ligand for its target, but, unless it causes a severe steric clash, it may also improve activity for off-targets – though hopefully less. Indeed, recent findings suggest that more lipophilic molecules tend to be more promiscuous than similarly-sized but less lipophlic molecules. On the other hand, due to the highly directional nature of polar interactions, a mismatched polar (enthalpic) interaction in an off-target is likely to be highly detrimental to binding.

The researchers consider two case studies involving HIV-1 protease inhibitors. In one example, adding two (non-polar) methyl groups improves the affinity of the inhibitor for its target as well as for two off-targets, though it improves the potency towards HIV-1 protease more, thus improving selectivity.

In the second case, a non-polar thioether is replaced with a polar sulfone. This slightly decreases the overall binding affinity for HIV-1 protease, but has a much larger negative effect on two off-targets, resulting in greater selectivity. In this case, the enthalpy of binding for HIV-1 protease is considerably improved, though the effect is compensated for by unfavorable changes in entropy. As the authors note, “even if a strong hydrogen bond does not contribute to affinity, it might contribute significantly to selectivity.”

Ideally you would want to use both strategies (improving affinity for your target and decreasing affinity for off-targets). However, since you probably don’t know all your off-targets, focusing on enthalpic binders may be the way to go, as mismatched polar interactions are likely to exclude lots of unknown off-targets.

Of course, two examples may not make a trend, but they do make a testable hypothesis. For example, there is a veritable plethora of kinase inhibitors with known specificity profiles: it would be interesting to correlate these with their thermodynamic profiles. But at any rate, this is yet another reason to hold down the hydrophobicity of your compounds.


Dr. Teddy Z said...

So, my cynical self always ask, "If I give this data to a medicinal chemist (enthalpic vs. entropic), how will he use it to decide which compounds to make?" To often, in my experience, we think we are being so clever with new metrics, new approaches, new parsing of data, but in the end what matters most is did the data get used in the decision to make new compounds? I would be curious to hear from molecule makers how they would use this knowledge in their decision making process.

Pete said...

My challenge to those who advocate the benefits of enthalpy-driven binding is: Please tell me how an isothermal physiological system 'senses' that the binding is enthalpy-driven. The contribution of an individual protein- ligand contact is not strictly an experimental observable and there. I've never seen any convincing data analysis that supports the links between enthalpy and polar interactions and between entropy and non-polar interactions. There are situations (e.g scale up of synthesis) where changes in enthalpy (and volume) are highly relevant.

I agree that excessive lipophilicity is a bad thing (although the trends are not always as strong as 'creative' ways of plotting the data might suggest). However, I'm not sure what calorimetry is adding to logP/D in terms of quantifying risk.