Towards rational molecular design: derivation of property guidelines for reduced acute aquatic toxicity

One of the most elusive yet significant goals of green chemistry is the routine design of commercially useful chemicals with reduced toxicological hazard. The main objective of this study was to derive property guidelines for the design of chemicals with reduced acute aquatic toxicity to multiple species. The properties explored included chemical solubilities, size, shape and molecular orbital energies. Physicochemical properties were predicted using Schrodinger's QikProp, while frontier orbital energies (HOMO, LUMO and HOMO–LUMO gap) were determined based on AM1 and DFT calculations using Gaussian03. Experimental toxicity data included acute toxicity thresholds (LC₅₀) for the fathead minnow (Pimephales promelas; 570 compounds), the Japanese medaka (Oryzias latipes; 285 compounds), a cladoceran (Daphnia magna; 363 compounds) and green algae (Pseudokirchneriella subcapitata, 300 compounds). Mechanistically-driven qualitative and quantitative analyses between the in-silico predicted molecular properties and in vivo toxicity data were explored in order to propose property limits associated with higher probabilities of acutely safe chemicals. The analysis indicates that 70–80% of the compounds that have low or no acute aquatic toxicity concern by EPA guidelines to the four species have a defined range of values for octanol-water partition coefficient (logP_o/w) and ΔE (LUMO–HOMO gap). Compounds with logP_o/w values less than 2 and ΔE (AM1) greater than 9 eV are significantly more likely to have low acute aquatic toxicity compared to compounds that do not meet these criteria. These results are mechanistically rationalized. Our work proposes design guidelines that can be used to significantly increase the probability that a chemical will have low acute toxicity to the four species studied, and potentially other aquatic species.