Drug design of novel molecules using a bioisosteric and de novo techniques - a comparison

Abstract

Rational drug design is an area of science that evolves continuously in order to answer contemporary demands for a decrease in novel drug discovery turnover time. Multiple drug design modalities exist which may be exploited in response to the parameters of specific drug design projects. Bioisosteric modification of existing molecules and de novo design are two such approaches, both of which were employed in parallel in this study which aimed to compare their scope and efficiency using Tricyclic Antidepressants (TCAs) and Selective Serotonin Reuptake Inhibiting (SSRIs) molecules as case studies. Results indicated that bioisosterically modified structures did not have a higher affinity for their cognate receptor when compared to the template structure while the de novo design yielded molecules that were markedly different to the template from a structural perspective, and which also bound to the cognate receptor with an affinity superior to that of the template. This study showed therefore that bioisosteric modification is of utility when minor structural variations are considered sufficiently relative to a template molecule, and could consequently be of utility in the acquisition of new patents, in the reduction of toxicity, or in the attainment of improved biological profiles. It indicated furthermore, the role of the de novo approach in the successful exploration of novel pharmacophoric space and in the generation of molecular structures with an affinity significantly greater than that of lead molecules for a target receptor.