A Thermodynamic Guide to Affinity Optimization of Drug Candidates

Abstract

Acommon starting point in drug development is the identification through screening or rational design of compounds that bind or exhibit some inhibitory activity against their intended targets. Often, those compounds bind to their targets with micromolar and sometimes weaker affinities. To become effective drugs, the binding affinities of those compounds need to be optimized by three or more orders of magnitude. This task is not a trivial one if one considers that it needs to be done while satisfying several stringent constraints, e.g., the molecular mass cannot substantially exceed 500 Da in order for the molecule to be orally bioavailable; the compound needs to exhibit appropriate target selectivity, appropriate membrane permeability and sufficient water solubility. Furthermore, the compound needs to exhibit an adequate pharmacokinetic profile, no toxicity, and so forth. These constraints considerably reduce the universe of chemical functionalities that can be utilized to achieve the optimization goals. In addition, at the thermodynamic level, chemical modifications that improve the binding enthalpy are usually accompanied by compensating entropy changes and vice versa, resulting in little or no gain in binding affinity. The identification of functionalities that carry the lowest enthalpy/entropy compensation is critical for affinity optimization. Since the binding affinity is the product of enthalpic and entropic contributions, it is possible for various ligands to have the same affinity but vastly different enthalpy/entropy profiles. While in theory, extremely high affinity can be achieved with arbitrary enthalpy/entropy combinations, the experience with HIV-1 protease inhibitors indicates that a strong favorable binding enthalpy is necessary. Furthermore, enthalpically optimized inhibitors have been shown to respond better to target mutations associated with drug resistance or naturally occurring polymorphisms without losing selectivity towards unwanted targets. It is evident that high affinity inhibitors characterized by strong favorable binding enthalpies are highly desirable. Consequently, the development of accurate rules with the ability to guide the affinity and enthalpic optimization of drug candidates is extremely important. This is the subject of this chapter.