pH‐Dependent Binding Modes Observed in Trypsin Crystals: Lessons for Structure‐Based Drug Design

Drug lead compound identification increasingly uses high-throughput screening in conjunction with computational methods. Hits found in this way are generally of low affinity (typically about 10−5 M) and require further development. Such low affinity can result in significant changes in binding mode upon change of experimental conditions: at pH 7, the Factor Xa inhibitor 1 (see picture) binds in the specificity pocket of trypsin through its pyridinyl group (yellow); at pH 8, the same pocket is occupied by the chloronaphthyl moiety (magenta), with a significant reorganization of the ligand binding site (circled).