Enhanced Bioactivity of Natural Products by Halogenation: A Database Survey and Quantum Chemistry Calculation Study

Natural products (NPs) have long
been the cornerstone
of drug discovery.
Halogenated organic NPs are limited, while around one-fourth of approved
chemical drugs are organohalogens. This suggests that the introduction
of halogens into NPs may enhance their potential for transformation
into drugs. In this study, we utilized a matched molecular pair (MMP)
approach alongside a database survey to investigate the impact of
halogenation on this transformation. The study revealed that halogenation
increased the bioactivity of 70.3% of NPs, with 50.3% exhibiting at
least a 2-fold enhancement. Halogen bonds (XBs) are prevalent between
organohalogens and their targets. To explore whether halogenated NPs
could form XBs with their targets, computational studies were performed
and demonstrated that halogenated NPs or NP-derived drugs formed strong
XBs with their targets, resulting in improved binding affinities.
This study highlights the considerable potential of introducing halogens
into NPs as a strategic approach for enhancing bioactivity and facilitating
the development of drugs.