One of the applications of the Surflex eSim3D technology is the ability to simultaneously align multiple ligands to generate a series of consensus alignments that serve as a binding pose hypothesis. This hypothesis can be used as a reference for subsequent compound library alignments.
This approach is useful for projects in which there is little to no structural information about the protein, but known active ligands are available.
For these binding pose hypothesis experiments, the best practice is to select a small number of similarly sized active ligands that are structurally diverse from each other. You must also make the assumption that these active ligands have the same binding mode i.e., they are binding to the same active site in the same fashion.
The binding hypotheses consider the estimated molecular strain, reflecting the degree to which a ligand’s predicted binding conformation deviates from the identified global minimum (using a variant of MMFF94s, implemented within the ForceGen conformer elaboration approach).
The underlying methodology for binding pose hypothesis generation is discussed in more detail in:
Ann and Ajay discuss the science behind and applications of the eSim molecular similarity method, a ligand-based drug design approach which considers surface-shape, electrostatics, and directionally sensitive hydrogen-bonding when comparing two molecules.
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