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.