Target-based analysis of ionization states of bioactive compounds

Abstract

A systematic analysis of ionization states of current bioactive compounds is presented. Ionization states were related to biological activities on the basis of high-confidence activity data. The majority of bioactive compounds were found to be basic or neutral under physiological conditions. In addition, chemical neighborhoods of active compounds frequently contained analogs with different ionization states that were activity-conservative. However, a variety of targets were identified that displayed clear preferences for specific ionization states in compounds active against them. In this context, notable differences in the distribution of ionization states were detected for compounds active against different target superfamilies. Furthermore, under physiological pH, differences in ionization states of active compounds were tolerated by many targets. However, in a number of instances, ionization states of highly and weakly potent compounds active against the same target were found to be distinct, providing guidelines for compound design and optimization.