Discriminating between Drugs and Nondrugs by Prediction of Activity Spectra for Substances (PASS)

Soheila Anzali, Gerhard Barnickel, Bertram Cezanne, Michael Krug, Dmitrii Filiminov, and Vladimir Poroiko (collaboration between Merck

and an academic institution)

Max Shneider – Case study

Overview Goal – better drug/nondrug classification at

beginning of drug discovery process (ADMET) Method - Used PASS, a computer system that

predicts more than 500 biological activities using regression Has a mean prediction accuracy of about 86%

2D compound representation – includes information on each atom and its neighbors

Training set – 5,000 drugs from WDI database and 5,000 nondrugs from ACD database

Test set filtering – removed items that were already in training set, had errors in structural formulas, etc.

Results Leave-one out (LOO) cross-validation

Mean prediction accuracy of 79.9% PASS vs Drugs

864 launched and registered compounds from Cipsline database Predicted 78.5% drugs, 21.5% nondrugs

PASS vs Nondrugs 9,484 compounds with reactive groups, low molecular weight, etc. Predicted 83.8% nondrugs, 16.2% drugs

PASS vs TOP-100 Drugs 88 compounds from top-100 prescription pharmaceuticals list Predicted 87.5% drugs, 12.5% nondrugs

Evaluating PASS with Cleaned Training Set Used filtered “Drugs” and “Nondrugs” test sets from above as training

sets instead of WDI and ACD LOO cross-validation – mean prediction accuracy of 89.9% vs TOP-100 Drugs - Predicted 94.5% drugs, 4.5% nondrugs

Discussion Chemical descriptors and algorithms in PASS provide

highly robust structure-activity relationships and reliable predictions

PASS is in good accordance with other approaches (Sadowsky and Kubinyi, Ajay)

PASS is relatively successful on new compounds that have nontraditional structures and/or belong to new chemical classes

Computation is fast – one compound can be predicted in 4 ms on a 300 MHz computer

Using PASS out of the box gives good results, but better discrimination might be possible with more specific drug information