Improving the odds of success in antitumoral drug development using scoring approaches towards heterocyclic scaffolds

One of the most commonly discussed topics in the field of drug discovery is the continuous search for anticancer therapies, in which small-molecule development plays an important role. Although a number of techniques have been established over the past decades, one of the main methods for drug discovery and development is still represented by rational, ligand-based drug design. However, the success rate of this method could be higher if not affected by cognitive bias, which renders many potential druggable scaffolds and structures overlooked. The present study aimed to counter this bias by presenting an objective overview of the most important heterocyclic structures in the development of anti-proliferative drugs. As such, the present study analyzed data for 91,438 compounds extracted from the Developmental Therapeutics Program (DTP) database provided by the National Cancer Institute. Growth inhibition data from these compounds tested on a panel of 60 cancer cell lines representing various tissue types (NCI-60 panel) was statistically interpreted using 6 generated scores assessing activity, selectivity, growth inhibition efficacy and potency of different structural scaffolds, Bemis-Murcko skeletons, chemical features and structures common among the analyzed compounds. Of the most commonly used rings, the most prominent anti-proliferative effects were produced by quinoline, tetrahydropyran, benzimidazole and pyrazole, while overall, the optimal results were produced by complex ring structures that originate from natural compounds. These results highlight the impact of certain ring structures on the anti-proliferative effects in drug design. In addition, considering that medicinal chemists usually focus their research on simpler scaffolds the majority of the time with no significant pay-off, the present study indicates several unused complex scaffolds that could be exploited when designing anticancer therapies for optimal results in the fight against cancer.