Investigation of the relationship between topology and selectivity for druglike molecules

There is a strong interest in drug discovery and development to advance the understanding of pharmacological promiscuity. Improved understanding of how a molecular structure is related to promiscuity could help to reduce the attrition of compounds in the drug discovery process. For this purpose, a descriptor is introduced that describes the structural complexity of a compound based on the size of its molecular framework (MF) in relation to its overall size. It is defined as the fraction of the size of the molecular framework versus the size of the whole molecule (f(MF)). It is demonstrated that promiscuity correlates with f(MF) for large f(MF) values. The observed correlation is not due to lipophilicity. To provide further explanation of this observation, it was found that the number of terminal ring systems in a compound is correlated with promiscuity. The analysis presented here might help medicinal chemists to improve the selectivity for compounds in drug discovery projects.