Current Topics in Medicinal Chemistry Special FBDD. TГіm tt - Enthalpy vs Entropy Enthalpy vГ entropy lГ cГЎc thut ng nhit ng mГ chГєng ta thng s dng vi cГЎc phn ng hГіa hc.If you have the resources, it may be worthwhile characterizing the thermodynamic profiles of your fragment hits, and вЂ“ perhaps вЂ“ looking more closely at those that show enthalpically-driven binding. Clausius 1865, entropie, en to contain, trope turning or transformation, 'transformation-contents' (trophy: enemy turning around, tropic: sun turns around at tropics of Cancer/Capricorn). Obtaining thermodynamic parameters for small-molecule protein interactions has historically been challenging, but in recent years miniaturization and improvements in technology have brought ITC into more non-specialist labs. the degree to which energy is wasted (dispersed) a measure of the unavailability of heat energy for work.

Compound 19 shows a highly favorable binding enthalpy, and is the most potent and ligand-efficient of any of the three elaborated molecules. However, this was a relatively modest boost for the more entropic compound 3 to compound 20, but considerably larger for the enthaplically-driven compound 2 to compound 19. In compound 3, the fluorine points towards the hydrophobic wall of the protein.ДЄdding a 4-benzylamide substituent onto each of these molecules led to improvements in activity.

Interestingly, the structure of compound 2 shows a specific interaction between the fluorine atom and a main-chain NH of the protein. The researchers determined high-resolution crystal structures for all three of these molecules bound to hCA II. In contrast, compound 3 has a similar enthalpy of binding as compound 1 but increased entropy. However, a look at the thermodynamic parameters reveals that the affinity of compound 2 is driven by a sizable improvement in enthalpic binding, partially offset by lowered entropy. If you were choosing between these fragments solely on the basis of affinity or ligand efficiency, it would be reasonable to choose compound 3, and in fact a search of the literature turned up 15 carbonic anhydrase inhibitors that contained the 3-fluorobenzenesulfonamide substructure and none that contained the 2-flurobenzenesulfonamide substructure. In contrast, adding a fluorine to the 3-position (compound 3) improves the potency by seven-fold and also improves the ligand efficiency. Adding a fluorine group to the 2-position of benzenesulfonamide (compound 2) improves the potency almost three-fold but lowers the ligand efficiency. Benzenesulfonamide (compound 1, below) is a known binder, and the researchers studied the thermodynamics of 20 derivatives of this molecule using isothermal titration calorimetry (ITC), taking care to generate high-quality binding data.

The researchers used human carbonic anhydrase (hCA II), a venerable work-horse of biophysical studies. In a new paper in ChemMedChem, Andrew Scott and colleagues at Pfizer show how fragments that owe more of their binding affinity to enthalpy make better starting points for optimization than do fragments whose binding is more entropic, even if the entropic fragment is more potent. Optimizing enthalpy is usually more difficult than optimizing entropy: engineering a polar interaction requires more precision than adding a bit of grease. On a (very) simplistic level, enthalpic binding comes via specific molecular interactions, such as hydrogen bonds, while entropic binding results from nonspecific hydrophobic interactions. Affinity, or binding energy, can be dissected into two components: enthalpy and entropy.

Assume the change is reversible and the temperature remains constant.The earliest stages of lead discovery usually focus on obtaining a molecule with decent affinity for a given target. Determine the change in entropy (in J/K) of water when 425 kJ of heat is applied to it at 50 oC.

Entropy vs enthalpy