New QSAR Approach to Describe Nitroaromatics Toxicity Authors: Viktor Kuz'min1, Eugene Muratov1, Leonid Gorb2, Mohammad Qasim2, Jerzy Leszczynski1 1 Jackson State University/Chemistry Department, United States 2 U.S. Army Corp of Engineers (USACE)/Engineer Research and Development Center (ERDC) Keywords: HiT QSAR, SiRMS models, nitroaromatics, risk assessment, toxicity The present study is devoted to the application of hierarchical technology for quantitative structure-activity relationships (HiT QSAR) for: (i) evaluation of the influence of structure on the toxicity of 28 nitroaromatic compounds, some of which belong to widely known explosives; (ii) prediction of toxicity for new nitroaromatic derivatives; and, (iii) analysis of the substitution character in nitroaromatic compounds’ influence on their toxicity in vivo. The 50 percent lethal dose concentration for rats (LD50) was used to develop QSAR models based on simplex representation of molecular structure. A comprehensive analysis of toxicity change as a function of substituents position and nature was carried out. Molecular fragments that promote and interfere with toxicity were defined on the basis of the obtained models. It was shown that interference of substituents in the benzene ring plays the determining role for toxicity. We concluded that HiT QSAR technology, on the basis of Simplex Representation of Molecular Structure (SiRMS), proved itself as a new and quite efficient tool to analyze different manifestations of nitroaromatics toxicity. Among the manifestations are comprehensive analysis of the substituents influence and contribution of electrostatic, hydrophobic, and der Waals interactions of toxicants with the biological target. Of special note is the predictive power of this technology, which now should be confirmed or disregarded by experimental verification. It was found that, in most cases, the insertion of fluorine and hydroxyl group into nitroaromatics increases the toxicity; the methyl group has an opposite influence. Chlorine influence on toxicity is ambiguous. Insertion of chlorine in ortho-position to nitro group leads to substantial toxicity increase. The next chlorine atom, in para-position to the previous one, promotes the strong toxicity decrease. We also concluded that the influence of substituents is substantially nonadditive. Point of Contact: Mohammad Qasim Research Chemist USACE/ERDC EP-P Bldg 3299 Vicksburg, MS 39180 601-634-3422 mohammad.m.qasim@erdc.usace.army.mil