Machine Learning Prediction of On/Off Target-driven Clinical Adverse Events.

Objective: Currently, 90% of clinical drug development fails, where 30% of these failures are due to clinical toxicity. The current extensive animal toxicity studies are not predictive of clinical adverse events (AEs) at clinical doses, while current computation models only consider very few factors with limited success in clinical toxicity prediction. We aimed to address these issues by developing a machine learning (ML) model to directly predict clinical AEs.

Methods: Using a dataset with 759 FDA-approved drugs with known AEs, we first adapted the ConPLex ML model to predict IC $_{50}^{}$ values of these FDA-approved drugs against their on-target and off-target binding among 477 protein targets. Subsequently, we constructed a new ML model to predict clinical AEs using IC $_{50}^{}$ values of 759 drugs' primary on-target and off-target effects along with tissue-specific protein expression profiles.

Results: The adapted ConPLex model predicted drug-target interactions for both on- and off-target effects, as shown by co-localization of the 6 small molecule kinase inhibitors with their respective kinases. The coupled ML models demonstrated good predictive capability of clinical AEs, with accuracy over 75%.

Conclusions: Our approach provides a new insight into the mechanistic understanding of in vivo drug toxicity in relationship with drug on-/off-target interactions. The coupled ML models, once validated with larger datasets, may offer advantages to directly predict clinical AEs using in vitro/ex vivo and preclinical data, which will help to reduce drug development failure due to clinical toxicity.