(Based on the research article “In Silico Phototoxicity Prediction of Drugs and Chemicals by using Derek Nexus and QSAR Toolbox” by Ahuja et al.).

Challenge of Phototoxicity

One of the less obvious risks in drug development is not how a medicine works inside the body, but how it behaves in the real world, particularly when exposed to sunlight. Certain compounds, on activation by ultraviolet (UV) radiation,  trigger painful rashes, burns, or long-term skin damage. This phenomenon, known as phototoxicity, results in reduced patient compliance, the abandonment of promising drug candidates, and regulatory challenges. In drug development, phototoxicity testing determines how a medicine behaves when exposed to sunlight.

Traditionally, phototoxicity testing has relied on animal models (mice, rats, guinea pigs) or established in vitro assays. While effectve, these methods are slow, costly, and ethically challenging. Each compound tested requires multiple experiments, skilled staff, animal housing facilities, chemical supplies, and specialized laboratory infrastructure. For industries where every month of delay can mean millions in losses, these traditional methods are becoming less sustainable. Moreover, with growing global pressure to minimize animal testing, there is an urgent demand for faster, cost-efficient, and ethically acceptable alternatives.

In Silico Testing Development with Derek Nexus and QSAR Toolbox

This is where in silico testing comes in. “In silico” simply means “within the computer.” Instead of running lengthy experiments in a lab, scientists feed the chemical structure of a compound into advanced predictive software and obtain a forecast of whether that compound is likely to cause phototoxic reactions. In this study, the team chose two recognized systems: Derek Nexus and the OECD QSAR Toolbox.

The researchers collected a diverse panel of 57 substances, including 30 known to cause phototoxicity and 27 known to be nonphototoxic. Notably, the researchers also had reference data for these compounds, including results from earlier animal studies, human clinical observations, and laboratory assays such as the 3T3 phototoxicity assay (Neutral Red Uptake test) and the reconstructed human epidermis (RhE) model, which mimics human skin. The goal was clear: evaluate if in silico platforms can speed up phototoxicity screening, delivering rapid, economical assessments that complement or partially replace traditional laboratory testing.

Results: Phototoxicity Testing Promises and Limitations

The results reveal that, for phototoxicity testing, Derek Nexus tends to be more conservative, rarely raising false alarms, but sometimes missing true dangers. QSAR Toolbox is more sensitive, catching more true risks, though at the cost of a few more false alarms. Therefore, used together, they provide a complementary safety net.

The findings of the study highlight the maturity and promise of computational toxicology. Both Derek Nexus and the QSAR Toolbox reached overall predictive accuracies of nearly 80%, which is impressive given the complexity of phototoxic mechanisms. These results suggest that in silico tools can be meaningfully integrated into early-stage safety evaluations. By identifying compounds with phototoxic potential before advancing to costly in vitro or in vivo testing, researchers can conserve resources, reduce animal use, and accelerate decision-making in drug development pipelines.

The study also aligns with the ICH S10 guideline on photosafety, which encourages early assessment of UV-related risks. Notably, regulators such as the EMA and FDA are increasingly open to computational methods as part of a tiered testing strategy, especially when combined with laboratory confirmation.