Acute Toxicity of Substituted 2‐(1H‐pyrazol‐1‐yl)acetanilides and Related Commercially Available Local Anesthetics Toward Mice. A GRIND/ALMOND‐Based 3‐D QSAR Study
Branko J. Drakulić, Christina Zãlaru, Mircea Iovu · QSAR & Combinatorial Science · 2008
Abstract Alignment‐free three‐dimensional quantitative structure–toxicity relationship models, developed on the basis of GRid INdependent Descriptors (GRIND), on acute toxicity data obtained by (i) oral administration of 25 pyrazolylacetanilides, and (ii) intravenous administration of 15 commercially available Local Anesthetics (LAs) to mice was reported. The most favorable interaction regions extracted from molecular interaction fields obtained with HBA, HBD, hydrophobic, and shape probes were correlated with toxicity data expressed as log[1/(LD50)] by partial Least Square Analysis (PLS). Variable selection was done by fractional factorial design. The best PLS models for set (i) comprises 3LV with r2=0.95 and q2=0.72; for set (ii) comprises 2LV with r2=0.95 and q2=0.58. Internal cross‐validation was done by using three random groups of compounds for each set. External predictivity of the second model was checked by a test set consists of eight structurally diverse compounds. The PLS model related to orally administrated set of compounds was compared with the corresponding one related to intravenously administrate drugs. Variables having high impact on each model, positively or negatively correlated with toxicities, were discussed and an attempt was made to link those variables with calculated ADME related properties of compounds, as well as with literature data that describes probable interaction of LA drugs with the homology modeled voltage‐gated sodium channels. According to the best of our knowledge this is first reported study that use GRIND methodology in structure–toxicity relationships on whole animals.