Leveraging nitrogen occurrence in approved drugs to identify structural patterns

The process of drug development and discovery is costly and slow. Although an understanding of molecular design principles and biochemical processes has progressed, it is essential to minimize synthesis-testing cycles. An effective approach is to analyze key heteroatoms, including oxygen and nitrogen. Herein, we present an analysis focusing on the utilization of nitrogen atoms in approved drugs.

The present work examines the frequency, distribution, prevalence, and diversity of nitrogen atoms in a dataset comprising 2,049 small molecules approved by different regulatory agencies (FDA and others). Various types of nitrogen atoms, such as sp³-, sp²-, sp-hybridized, planar, ring, and non-ring are included in this investigation.

The results unveil both previously reported and newly discovered patterns of nitrogen atom distribution around the center of mass in the majority of drug molecules.

This study has highlighted intriguing trends in the role of nitrogen atoms in drug design and development. The majority of drugs contain 1-3 nitrogen atoms within 5Å from the center of mass (COM) of a molecule, with a higher preference for the ring and planar nitrogen atoms. The results offer invaluable guidance for the multiparameter optimization process, thus significantly contributing toward the conversion of lead compounds into potential drug candidates.