Ecotoxicological Modeling, Ranking and Prioritization of Pharmaceuticals Using QSTR and i‐QSTTR Approaches: Application of 2D and Fragment Based Descriptors

Abstract

This paper is dedicated to Prof. Paola Gramatica on the occasion of her retirement.Abstract: There is a huge lack of experimental data on ecotoxicity of pharmaceuticals, while existing resources are insufficient to gather these data against all possible environmental endpoints. Computational tools such as quantitative structure-toxicity relationship (QSTR) can help us to a great extent to overcome this problem through filling of data gaps. In the current study, QSTR models have been developed for toxicity of 260 diverse pharmaceuticals on three different trophic level species namely algae, daphnia and fish, using partial least squares (PLS) regression approach with 2D descriptors selected through a genetic algorithm approach in order to study underlying chemical features responsible for the observed acute toxicity. The final obtained statistically reliable QSTR models were extensively validated following the OECD guidelines. Interspecies quantitative structure-toxicity-toxicity (QSTTR) models were also developed using genetic algorithm followed by multiple linear regression (GA-MLR) approach to check for the pattern of responses observed as we move across the hierarchy of genetics in different taxonomical class. The obtained interspecies models were finally utilized to fill the data gaps for 260 pharmaceuticals, where experimental data were missing for at least one of the endpoints. Finally, a prioritized list for 7106 existing drug like substances was prepared by predicting their acute toxicity using developed QSTR models.

Prior Knowledge for Predictive Modeling: The Case of Acute Aquatic Toxicity

“…The higher toxicity values have often been associated with increased lipohilicity. ,, The most toxic compounds were hydrophobic and acted as hydrogen-bonding or electron acceptors (e.g., hydrophobic nitroaromatic compounds with halogen and amino substituents ,,,, ). Khan et al (2019) have advised that if a hydrophobic group is necessary during the design of a drug compound, a higher polarity substitution should be preferred. Voutchkova et al.…”

“…50,88,89 The most toxic compounds were hydrophobic and acted as hydrogen-bonding or electron acceptors (e.g., hydrophobic nitroaromatic compounds with halogen and amino substituents 52,53,81,90,91 ). 92 have advised that if a hydrophobic group is necessary during the design of a drug compound, a higher polarity substitution should be preferred. Voutchkova et al ( 2011) 93 have suggested keeping logPo/w < 2 and ΔE (LUMO−HOMO) > 9 eV to increase the likelihood of designing a compound with low aquatic toxicity.…”

What Approaches Should be Used to Prioritize Pharmaceuticals and Personal Care Products for Research on Environmental and Human Health Exposure and Effects?

“…Given the expense and other resources required to conduct toxicity tests, ecotoxicity/toxicity data for PPCPs are limited in terms of both the number of PPCPs tested and the types of apical effects examined. Therefore, researchers predict the potential hazards of PPCPs via in silico quantitative structural–activity relationship (QSAR) modeling, which is used, for example, in the USEPA's PBT Profiler, CTV Predictor, and EPISuite software including BIOWIN, BCFBAF, and ECOSAR (Diamond et al, 2011; Golbaz et al, 2021; Kar et al, 2018; Khan, Benfenati, et al, 2019; Khan, Kar, et al, 2019). In particular, the current hazard‐based prioritization studies rely heavily on predicted PBT data using various QSAR models, which remain to be experimentally validated (Guo et al, 2016).…”

The Influence of Structural Patterns on Acute Aquatic Toxicity of Organic Compounds

“…Since 2006, the European regulation on the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) [2] requires a mandatory preliminary assessment of their toxicity to aquatic organisms before starting production and trade. To address this challenge, many QSAR studies have been conducted and reported for different aquatic toxicity endpoints [3][4][5][6][7][8][9][10][11][12][13].…”