The Impact of Physicochemical and Molecular Properties in Drug Design: Navigation in the “Drug-Like” Chemical Space

Abstract

Physicochemical and molecular properties influence both pharmacokinetic and pharmacodynamic process, as well as drug safety, often in a conflicting way. In this aspect the current trend in drug discovery is to consider ADME (T) properties in parallel with target affinity. The concept of “drug-likeness” defines acceptable boundaries of fundamental properties formulated as simple rules of thumb, in order to aid the medicinal chemist to prioritize drug candidates. Special attention is given to lipophilicity and molecular weight, since there is a tendency for those parameters to increase in regard to complex compounds generated by new technologies, with potential consequences in bioavailability, while high lipophilicity is also associated with undesired effects. Such rules have the advantage to be very simple and are easy to interpret; however their drawback is that they do not take into consideration uncertainties in measurements and calculations as well as the receptor requirements. The case of PPARs, a nuclear receptor family, is discussed in detail in regard to the chemical space covered by the ligands, focusing on the high demands of the ligand binding domain in both lipophilicity and molecular size. Such paradigms indicate that it would be more appropriate to adapt drug-like properties according to specific drug discovery projects.