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. The earliest stages of lead discovery usually focus on obtaining a molecule with decent affinity for a given target.
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