Structure-based drug design has evolved over the last 40 years to an important concept in medicinal chemistry being mainly used in the early drug discovery phase, the so-called hit-to-lead optimization. Upon determination of the binding mode of an initial ligand bound to its target which generally provides valuable information on the ligand’s key interactions, a series of derivatives is synthesized to deduce a first structure-activity-relationship. The design of the compounds is usually based on the assumption that the binding mode is retained throughout the SAR exploration. In most of the cases the retrieved affinity data are in agreement with the initially derived model, consequently the hypothesis that similar ligands bind in similar fashion is widely accepted within the medicinal chemistry community. Yet, there are examples in which the actually determined affinity data at first glance cannot be fitted to the design hypothesis thus resulting in an inconclusive SAR, which often might lead to termination of all further hit-to-lead optimization efforts. A few case studies will be discussed for which the apparent discrepancies between the determined affinity data and the binding hypotheses have been unraveled indicating that within a congeneric ligand series there might exist more than one distinct binding mode. Hence, detecting and exploiting these might open up new starting points for the head-to-lead optimization process for a given target.

Similar ligands bind in similar fashion: Sometimes they don’t!

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.