The order-of-magnitude increase or decrease in hydrogen-bond-acceptor-strength induced by single-atom changes underscores the utility of prospective pK BHX prediction in silico. for the PI3Kα kinase. Based on structural data, the authors hypothesized that introducing a nitrogen at "N 1 " (Figure ) on the five-membered ring might induce lone-pair repulsion with several carbonyl groups found in other kinase binding pockets and thus lower the compound's affinity for these "anti-targets." A variety of azaarene linkers were tested against PI3Kα and the kinase anti-target KDR, and the addition of a nitrogen did indeed increase the selectivity for PI3Kα (Figure ). Nitrogens that were better hydrogen-bond acceptors were found to Hydrogen-bond-basicity calculations can be used to rationalize these effects (Figure ).