The development of computational methods that can estimate the various pharmacodynamic and pharmacokinetic parameters that characterise the interaction of drugs with biological systems has been a highly pursued objective over the last 50 years. Among all, methods based on ligand information have emerged as simple, yet highly efficient, approaches to in silico pharmacology. With the recent impact on the identification of new targets for known drugs, they are again the focus of attention in chemical biology and drug discovery.

Nuclear receptors form a family of ligand-activated transcription factors that regulate a wide variety of biological processes and are thus generally considered relevant targets in drug discovery. We have constructed an annotated compound library directed to nuclear receptors (NRacl) as a means for integrating the chemical and biological data being generated within this family. Special care has been put in the appropriate storage of annotations by using hierarchical classification schemes for both molecules and nuclear receptors, which takes the ability to extract knowledge from annotated compound libraries to another level. Analysis of NRacl has ultimately led to the identification of scaffolds with highly promiscuous nuclear receptor profiles and to the classification of nuclear receptor groups with similar scaffold promiscuity patterns. This information can be exploited in the design of probing libraries for deorphanization activities as well as for devising screening batteries to address selectivity issues.

The recent explosion of data linking drugs, proteins, and pathways with safety events has promoted the development of integrative systems approaches to large-scale predictive drug safety. The added value of such approaches is that, beyond the traditional identification of potentially labile chemical fragments for selected toxicity end points, they have the potential to provide mechanistic insights for a much larger and diverse set of safety events in a statistically sound nonsupervised manner, based on the similarity to drug classes, the interaction with secondary targets, and the interference with biological pathways. The combined identification of chemical and biological hazards enhances our ability to assess the safety risk of bioactive small molecules with higher confidence than that using structural alerts only. We are still a very long way from reliably predicting drug safety, but advances toward gaining a better understanding of the mechanisms leading to adverse outcomes represent a step forward in this direction.

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

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