Assessing activity and toxicity of drugs in silico based on DNA structure

Abstract

One of the biggest challenges in pharmaceutical development is finding drug candidates with a desired activity or efficacy balanced with low toxicity or side-effects. Despite the enormous effort and cost required to get drugs to market, numerous drugs have been abandoned due to unanticipated, untoward effects. Clearly, technologies are needed that can identify safe and effective pharmaceutical candidates early in the drug pipeline. Our laboratory has developed a computer modeling technology that can be used to screen small-molecule ligands for certain desired activities as well as certain toxicities. The technology utilizes modeling of the intercalation of molecules into DNA to create efficacy and toxicity search engines and is grounded by two fundamental observations. First, intercalation has been shown to be integral in the action of drugs that act in concert with nuclear enzymes, e.g., topoisomerases. Second, evidence is mounting that intercalation facilitated by nuclear receptors bound to natural ligands is a critical part of their genomic mode of action. To date, two classes of search engines have been created, i.e., those that can be used to identify: (1) efficacious molecules, e.g., antibiotics, estrogens, androgens, glucocorticoids, thyroid drugs, antidepressants, antihistamines, and sedatives, and (2) toxic molecules, e.g., certain carcinogens and genotoxins. Here, we describe the creation of two prototype search engines (the estrogen efficacy and arene oxide genotoxicity search engines) and illustrative results of searches of three-dimensional databases. Of particular interest is the specificity of the search engines and their capacity to identify widely different, and in some cases obscure, structures having the same activities. Taken as a whole, future drug discovery research is likely to focus on methods to assess DNA intercalation as a salient feature of selecting safe and effective drug candidates.