Pharmacophore Hypotheses and Molecular Comparisons

The structure of the binding pocket determines which functional groups on the side of the ligand are necessary for successful binding to a protein. The starting point from which a pharmacophore is derived can be either the ligand or the protein structure. The allowed and forbidden regions of a hypothetical binding pocket can be defined by superimposing active and inactive small molecule ligands from a series of related compounds. Logical operations on the differences in volume can be used to guide the design of optimized ligands. Flexible molecules that can adopt different conformations pose a special challenge in superpositions. As part of the superposition procedure, the molecules must be energy minimized or, alternatively, multiple conformations must be evaluated. Alternatively, a set of molecules can be superimposed by assigning pharmacophoric groups and systematically rotating around all open-chain single bonds to find a common orientation in the active-analog approach. Care must be taken to ensure that one is not misled by molecules that appear to be similar in terms of their chemical formula. It is not the molecular skeleton itself that is important for molecular recognition, but rather the interacting functional groups at the binding pocket. The role of water in binding should not be underestimated. The superposition of molecules can also be considered in terms of their molecular recognition properties. Synthesizing a structurally rigid analog (or analogs) can help define and validate the pharmacophore assignment and determine the biologically active conformation. Binding “hot spots” can be found by studying the protein. This is done by mapping the binding pocket with small molecules and probes with different properties. These give an idea of what type of molecule might succeed in binding to the target protein. The Cambridge database of small molecule crystal structures provides valuable insights into preferred interaction geometries. Such information is of great relevance for protein-ligand complexes, as the forces responsible for crystal packing are the same as for non-binding drug-protein interactions. There are a number of databases that can be searched using a 3D pharmacophore as a query. Typically, commercially available compounds are screened first. If they show activity against a particular protein of interest, they can be purchased and tested. Hopefully, they will provide a starting point for lead discovery. https://sn.pub/0bzx5y