The Recognition of Identical Ligands by Unrelated Proteins

Abstract

The binding of drugs and reagents to off-targets is well-known. Whereas many off-targets are related to the primary target by sequence and fold, many ligands bind to unrelated pairs of proteins, and these are harder to anticipate. If the binding site in the off-target can be related to that of the primary target, this challenge resolves into aligning the two pockets. However, other cases are possible: the ligand might interact with entirely different residues and environments in the off-target, or wholly different ligand atoms may be implicated in the two complexes. To investigate these scenarios at atomic resolution, the structures of 59 ligands in 116 complexes (62 pairs in total), where the protein pairs were unrelated by fold but bound an identical ligand, were examined. In almost half of the pairs, the ligand interacted with unrelated residues in the two proteins (29 pairs), and in 14 of the pairs wholly different ligand moieties were implicated in each complex. Even in those 19 pairs of complexes that presented similar environments to the ligand, ligand superposition rarely resulted in the overlap of related residues. There appears to be no single pattern-matching “code” for identifying binding sites in unrelated proteins that bind identical ligands, though modeling suggests that there might be a limited number of different patterns that suffice to recognize different ligand functional groups.

Multi‐target Fragments Display Versatile Binding Modes

“…In addition, a large affinity difference is observed between the complexes (BindingDB reports IC 50 values of 0.003–8.3 μM for CAH2 and 164 μM for the chitinase). A similar example was also found by Barelier and colleagues who examined the binding of ligands to unrelated proteins . Comparing the binding modes of AZM in human CAH2 to AZM bound to a highly dissimilar carbonic anhydrase from Coccomyxa sp PA .…”

Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40

“…By the application of a combined binding energy cutoff, 749 hits remained, which were further reduced to 91 that showed high binding affinity for both EBOV proteins. Recent crystallography analyses also recognised identical ligands for different proteins [57]. The present study revealed a varying trend in docking results obtained against both Ebola viral proteins (VP35 and VP40) of the Zaire strain.…”

Machine learning models identify molecules active against the Ebola virus in vitro

“…Instead, we prefer to reference recently published crystallographic analyses 75 demonstrating that small molecules may bind multiple proteins in different types of binding sites and with distinct conformations to ultimately facilitate molecular repurposing. While it would be most desirable to repurpose an approved drug and, thus, catapult a discovery effort into a Phase II trial, one should not ignore the significance of utilizing the discovery of a new use for an old drug to seed efforts in the lead optimization phase 76 .…”