Development of QSAR models for microsomal stability: identification of good and bad structural features for rat, human and mouse microsomal stability.
High throughput microsomal stability assays have been widely implemented in drug discovery and many companies have accumulated experimental measurements for thousands of compounds. Such datasets have been used to develop in silico models to predict metabolic stability and guide the selection of promising candidates for synthesis. This approach has proven most effective when selecting compounds from proposed virtual libraries prior to synthesis. However, these models are not easily interpretable at the structural level, and thus provide little insight to guide traditional synthetic efforts. We have developed global classification models of rat, mouse and human liver microsomal stability using in-house data. These models were built with FCFP_6 fingerprints using a Naïve Bayesian classifier within Pipeline Pilot. The test sets were correctly classified as stable or unstable with satisfying accuracies of 78, 77 and 75% for rat, human and mouse models, respectively. The prediction confidence was assigned using the Bayesian score to assess the applicability of the models. Using the resulting models, we developed a novel data mining strategy to identify structural features associated with good and bad microsomal stability. We also used this approach to identify structural features which are good for one species but bad for another. With these findings, the structure-metabolism relationships are likely to be understood faster and earlier in drug discovery.
Hu
Yongbo
Y
Department of Computational Chemistry and Chemoinformatics, Wyeth Research, Pearl River, NY 10965, USA. huy2@wyeth.com
Unwalla
Ray
R
Denny
R Aldrin
RA
Bikker
Jack
J
Di
Li
L
Humblet
Christine
C
D000818:Animals; D055808:Drug Discovery; D004784:Environmental Monitoring; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
D004364:Pharmaceutical Preparations