The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations.
Approaches to improve the efficiency of molecular optimizations have received great attention and numerous efficiency metrics have been introduced to assist in this effort. Optimization of properties is equally important to optimization of potency and therefore these metrics contain potency versus property calculations. Widespread use of a metric does not guarantee its accuracy and a further understanding of which, if any, metric increases the probability of success was sought. An analysis of LE, LELP and LipE based on theoretical and experimental data was performed demonstrating that LipE most strongly correlates with compound quality as defined by enthalpy-driven binding. The basis for the prioritization of LipE over other metrics in enthalpic optimizations is described.
Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: michael.shultz@novartis.com.
Michael D
MD
Shultz
D015195:Drug Design; D008024:Ligands; D008055:Lipids / Q000737:chemistry*; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013816:Thermodynamics
D008024:Ligands; D008055:Lipids; D004364:Pharmaceutical Preparations
Composite parameters; Enthalpy; Ligand efficiency; Lipophilic efficiency; Thermodynamics