Impact of lipophilic efficiency on compound quality.
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.
Discovery Chemistry, Gedeon Richter plc, 19-21 Gyömrői út, H-1103 Budapest, Hungary.
Akos
A
Tarcsay
Kinga
K
Nyíri
György M
GM
Keseru
D001693:Biological Transport, Active; D002491:Central Nervous System Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D002627:Chemistry, Physical; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions; D008861:Microsomes / Q000378:metabolism; D000442:Octanols; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water
D002491:Central Nervous System Agents; D000442:Octanols; D004364:Pharmaceutical Preparations; D014867:Water