Molecular topology, a novel descriptor for compound quality assessment

The pharmaceutical industry is currently facing a high clinical attrition rate. In order to prevent the late-stage clinical failure, many investigations on compound quality and druglikeness of compounds have been carried out. It has been widely accepted that molecular size and lipophilicity plays an important role in compound quality. Many attempts have been done to find out other factors which can influence compound quality beyond size and lipophilicity. Recently, a molecular topology concept has been put forward and its influence on compound quality has been investigated. It has been shown that drugs have higher fraction of compounds with only one ring system compared to clinical candidate and bioactive compounds. As an extension to the previous studies, the aim of this project is to further investigate how the molecular topology influences some of the most important physicochemical properties of molecules as well as the compound potency efficiency indices in general. Our results show that among reported molecules in the literature, compounds with only one ring system are smaller in size, less lipophilic and therefore has a higher probability to be less toxic. Interestingly compounds which have a simple topology also show advantage in terms of potency efficiency such as ligand efficiency (LE), ligand lipophilic efficiency (LLE) and ligand-efficiency-dependent lipophilicity index (LELP) compared with compounds which have a more complex topology. Thus a novel hypothesis why compounds with only one ring system are abundant among drugs has been proposed. On average molecules with only one ring system seems to bind more strongly to its protein target; this might reduce the necessary size of the molecule to reach a certain potency level. The reduction in size and lipophilicity reduces the risk of failure in clinical trials.