Analyzing Oxygen Atom Distribution in FDA‐Approved Drugs to Enhance Drug Discovery Strategies

Despite advancements in molecular design rules and understanding biochemical processes, the field of drug design and discovery seeks to minimize the number and duration of synthesis-testing cycles to convert lead compounds into drug candidates. A promising strategy involves gaining insightful understanding of key heteroatoms such as oxygen and nitrogen. This work presents a comprehensive analysis of oxygen atoms in approved drugs, aiming to streamline drug design and discovery efforts. The study examines the frequency, distribution, prevalence, and diversity of oxygen atoms in a dataset of 2049 small molecules approved by the FDA and other agencies. The analysis focuses on various types of oxygen atoms, including sp³, sp²-hybridized, ring, and nonring. In general, existence of sp³-O slightly outperforms sp²-O, which is associated with balancing various factors such as flexibility, solubility, stability, and pharmacokinetics, in addition to activity and selectivity. In approved drugs, majority of oxygen atoms are present within 4 Å from the COM of the molecule. This analysis offers valuable understanding of oxygen distribution, which could be used during the multiparameter optimization process, facilitating the transformation of a hit/lead compound into a potential drug candidate.