Investigation of the influence of molecular topology on ligand binding

Molecular topology class has previously been put forward as a new concept of describing compound quality and it has been shown that compared to general bioactive compounds, drugs is more similar to natural products and human metabolites in terms of molecular topology class distribution, in which they are enriched with compounds having only one ring system. To further understand how the molecular topology is influencing the drug discovery process, we have investigated the compound potency of different molecular topologies in published chemical patents. Our study shows that the potency for compounds having one ring system is higher compared to compounds that have more than one ring system. Compounds with one ring system are significantly less lipophilic and smaller compared to compounds with several ring systems. Further the influence of the molecular topology on ligand efficiency (LE), ligand lipophilic efficiency (LLE) and ligand-efficiency-dependent lipophilicity (LELP) was also analyzed and it was found that on average compounds with fewer ring systems and in particular compounds with only one ring system show consistently better LE, LLE and LELP. The results suggest that compounds with fewer ring systems and in particular compounds with only one ring system have good properties and that they might be useful starting point for drug discovery projects.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (138 K)Download as PowerPoint slideHighlights► The influence of molecular topology on several ligand binding efficiency indices (LE, LLE, LELP) were studied. ► Compounds with fewer ring systems and in particular compounds with only one ring system show consistently better LE, LLE and LELP. ► Compounds with fewer ring systems and in particular compounds with only one ring system have good properties and might be useful starting point for drug discovery projects.