QSAR with quantum topological molecular similarity indices: toxicity of aromatic aldehydes to Tetrahymena pyriformis

Abstract

Extensive production and utilization of aromatic aldehydes and their derivatives without proper certification is alarming with regard to environmental safety. This concern motivated our construction of predictive quantitative structure–activity relationship (QSAR) models for the toxicity of aldehydes to the ecologically important species Tetrahymena pyriformis. Quantum topological molecular similarity (QTMS) descriptors, along with the lipid-water partition coefficient (log K _o/w), were used as predictor variables. The QTMS descriptors were calculated at different levels of theory including AM1, HF/3-21G(d), HF/6-31G(d), B3LYP/6-31 + G(d,p), B3LYP/6-311 + G(2d,p) and MP2/6-311+G(2d,p). The data set of 77 aromatic aldehydes was divided into a training set (n = 58) and a test (n = 19) set, and 58 models were developed using partial least squares (PLS) and genetic partial least squares (G/PLS). We evaluated the overall predictive capacity of the models based on leave-one-out predictions for the training set compounds and model derived predictions for the test set compounds. For both PLS and G/PLS, the models built at the HF/6-31G(d) level show better predictivity (based on overall prediction) than the models developed at any of the other five levels. Further validation was also performed utilizing (process and model) randomization tests. We show that improved predictive QSAR models for aldehydic toxicity to Tetrahymena pyriformis can be generated using QTMS descriptors along with log K _o/w.

Keywords:

• QTMS
• QSAR
• ab initio
• aldehydes
• QSPR
• external validation
• electron density
• atoms in molecules
• quantum chemical topology

Acknowledgements

Financial assistance from the Ministry of Human Resource Development, Government of India, New Delhi in the form of a scholarship to SK is gratefully acknowledged. We also thank the EPSRC (GB) and GlaxoSmithKline for financial support for APH.