ABSTRACT
The high attrition rates in drug development have presented a challenge to the pharmaceutical industry. This chapter describes a comprehensive in silico target safety assessment (TSA) approach to predict the safety issues that could arise from the modulation of a drug target. The toxicological risks identified can be used to make strategic choices about the progression of target–drug combinations and for the design of toxicity studies in the drug discovery pipeline. Off-target effects are due to nonselective binding of the drug that modulates the intended target. Compound-based toxicity may be of less concern at early stages of drug discovery because integrated safety assays in lead optimization cycles will ensure the design of compounds with a more favorable efficacy/toxicity profile. Both desired and adverse effects can be governed by interactions of a drug with many, often unrelated, targets. The ultimate aim of a TSA is to identify those safety liabilities that need immediate monitoring and de-risking during drug discovery.
