Steric and electronic criteria for teratogenicity of short chain aliphatic acids

Esters of short chain aliphatic acids are commonly used in industry as solvents which are easily metabolized to their acid analogs. Some of these aliphatic acids are also by‐products of industrial products, e.g., 2‐ethyl hexanoic acid is a metabolite of the plasticizer diethylhexyl phthalate and methoxy acetic acid is the principal metabolite of the glyco ether, 2‐methyl ethanol. Many of these aliphatic acids exhibit a variety of toxic effects. Cytochrome P450 is involved in the metabolism of aliphatic acids resulting in liver toxicity by formation of a toxic metabolite. These acids also act as sedatives, possibly by occupying a hydrophobic site in the brain. Certain aliphatic acids have been shown to cause teratogenic effects in laboratory animals for which the mechanism is as yet unknown. The techniques of computational chemistry can be useful in helping to formulate such mechanisms and ultimately for computer‐aided risk assessment of potentially toxic compounds. The current study focuses on developing reliable molecular indicators of the teratogenic behavior of selected aliphatic acids, by investigating the role of conformational, physical, and electronic properties. The geometries of the aliphatic acids used for analysis were optimized using CHARMm and AM1. Our results show that p K a and log P do not seem to be reliable modulators of teratogenic potency. By contrast, the conformation of the acid analogs, especially near the acid group, appears to be important for activity. These results implicate a possible mechanism of action involving a conformationally specific binding site or carrier protein.