Impact of Lipophilic Efficiency on Compound Quality

Citations Over TimeTop 1% of 2012 papers

Abstract

Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs.

Related Papers

• → ADME of Biologics—What Have We Learned from Small Molecules?(2012)73 cited
• → Applications of high-throughput ADME in drug discovery(2004)149 cited
• → ADME Optimization and Toxicity Assessment in Early- and Late-Phase Drug Discovery(2009)83 cited
• → Transporter-Mediated Drug–Drug Interactions(2011)75 cited
• → Fundamental Concepts in Clinical Pharmacology(2010)8 cited