![]() The Difficulties in Enthalpic Optimization If this is the case, why are drug candidates not enthalpically-optimized from the start? Why not make the first in class also the best in class? New thermodynamic-based platforms are beginning to address those issues. It appears that the molecular interactions reflected in a better binding enthalpy are critical for the development of improved drugs. A better enthalpic character also indicates a transformation in the type of interactions that determine binding. ![]() While the primary motivation to develop best in class compounds is certainly not a better binding enthalpy, but rather, much better potency, higher selectivity, better pharmacokinetics or a superior drug resistance profile, it is noteworthy that at the end, the resulting compounds have more favorable binding enthalpies. Nevertheless, examination of the evolution of FDA-approved HIV-1 protease inhibitors as well as statins, the two classes of drugs for which complete thermodynamic information has been published, suggests that best in class compounds that come into the market after several years are enthalpically better optimized than the original first in class compounds. As a result, the recent trend has been towards increasingly hydrophobic, poorly soluble, entropically-optimized drug candidates. The binding entropy on the other hand, being dependent primarily on the hydrophobic effect, is easier to optimize and is less affected by compensating enthalpy changes. First, the forces that contribute to the binding enthalpy are difficult to optimize and, second, if an enthalpic improvement is actually made, it is often not reflected in better affinity, because the enthalpy gain is compensated by an entropy loss. Several complicating factors are present. While the simultaneous optimization of enthalpy and entropy is the clear goal, the experience of many pharmaceutical laboratories has shown that this goal is difficult to achieve. However, Δ G is the sum of two different terms (Δ G = Δ H – TΔ S) and, consequently, extremely high affinity is only achieved when both enthalpy (Δ H) and entropy (Δ S) contribute favorably to binding. Binding affinity, K a, is dictated by the Gibbs energy of binding (Δ G), K a = e − Δ G R T.
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