The Binding Thermodynamics of Drug Candidates

The affinity optimization of drug candidates is a major goal in drug development. Affinity optimization is not a simple task because it needs to adhere to constraints that maintain or improve the drug-like character of the compound. The binding affinity is dictated by the Gibbs energy of binding. Drug molecules are composed of polar and nonpolar (carbon) atoms and they contribute very differently to the enthalpy change. In binding, two processes occur simultaneously: desolvation and the formation of drug/protein interactions. Two terms are of major concern from an engineering point of view: the solvation/desolvation entropy and the conformational entropy. The desolvation of both polar and nonpolar groups is favorable to binding. The Lipophilic Efficiency (LipE) is essentially a measurement of the binding affinity minus the hydrophobicity of a compound. Measuring the binding enthalpy provides an immediate account of the enthalpic efficacy of the polar functionalities.