Escape from Flatland 2: complexity and promiscuity

TLDR

Toxicity drives clinical attrition, and promiscuity—linked to toxicity—is influenced by descriptors such as ionization and logP, whose understanding can help mitigate drug deficiencies. The study investigates how molecular complexity, quantified by Fsp3 and chiral carbon count, relates to promiscuity and CYP450 inhibition. The authors assess this relationship by measuring complexity with Fsp3 and chiral carbon count and evaluating its impact on promiscuity and CYP450 inhibition. They find that higher complexity reduces both promiscuity and CYP450 inhibition.

Abstract

Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A number of molecular descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compounds as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic.