Analysis of the Acid/Base Profile of Natural Products from Different Sources

For many years drug discovery and other areas in chemistry have successfully relied on natural products. Recent advances in computational methods have made possible to study the chemical space of natural products from different sources. Ionizable acidic and basic functional groups heavily influence physicochemical properties and thus a molecule's absorption, distribution, metabolism, excretion, and toxicity characteristics as well as their affinity for biological targets. This work reports the generation and critical comparison of the acid/base profiles of ten chemical databases including seven natural products sets from different origins, a set of semisynthetic compounds, a collection of approved drugs, and a compendium of food chemicals. Similarities were found in the proportion of the main charge state categories among the natural products databases with few differences in their pK_a distributions. Clear differences were observed between natural products and the approved drugs and semi-synthetic natural products databases, whereas natural products share some trends with the food chemical database. We noted that the natural products collections comprise around 45 % of neutral compounds. The proportion of single acids was approximately twice that found for FDA drugs, and they demonstrated a similar distribution of pK_a values. In contrast to drugs, only 5 % of compounds among the natural products sets had a single basic group. Likewise, simple ampholytes were less prevalent in the natural products databases relative to drugs.