J Chem Inf Model - Encoding protein-ligand interaction patterns in fingerprints and graphs.


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We herewith present a novel and universal method to convert protein-ligand coordinates into a simple fingerprint of 210 integers registering the corresponding molecular interaction pattern. Each interaction (hydrophobic, aromatic, hydrogen bond, ionic bond, metal complexation) is detected on the fly and physically described by a pseudoatom centered either on the interacting ligand atom, the interacting protein atom, or the geometric center of both interacting atoms. Counting all possible triplets of interaction pseudoatoms within six distance ranges, and pruning the full integer vector to keep the most frequent triplets enables the definition of a simple (210 integers) and coordinate frame-invariant interaction pattern descriptor (TIFP) that can be applied to compare any pair of protein-ligand complexes. TIFP fingerprints have been calculated for ca. 10,000 druggable protein-ligand complexes therefore enabling a wide comparison of relationships between interaction pattern similarity and ligand or binding site pairwise similarity. We notably show that interaction pattern similarity strongly depends on binding site similarity. In addition to the TIFP fingerprint which registers intermolecular interactions between a ligand and its target protein, we developed two tools (Ishape, Grim) to align protein-ligand complexes from their interaction patterns. Ishape is based on the overlap of interaction pseudoatoms using a smooth Gaussian function, whereas Grim utilizes a standard clique detection algorithm to match interaction pattern graphs. Both tools are complementary and enable protein-ligand complex alignments capitalizing on both global and local pattern similarities. The new fingerprint and companion alignment tools have been successfully used in three scenarios: (i) interaction-biased alignment of protein-ligand complexes, (ii) postprocessing docking poses according to known interaction patterns for a particular target, and (iii) virtual screening for bioisosteric scaffolds sharing similar interaction patterns.

Resumo Limpo

herewith present novel univers method convert proteinligand coordin simpl fingerprint integ regist correspond molecular interact pattern interact hydrophob aromat hydrogen bond ionic bond metal complex detect fli physic describ pseudoatom center either interact ligand atom interact protein atom geometr center interact atom count possibl triplet interact pseudoatom within six distanc rang prune full integ vector keep frequent triplet enabl definit simpl integ coordin frameinvari interact pattern descriptor tifp can appli compar pair proteinligand complex tifp fingerprint calcul ca druggabl proteinligand complex therefor enabl wide comparison relationship interact pattern similar ligand bind site pairwis similar notabl show interact pattern similar strong depend bind site similar addit tifp fingerprint regist intermolecular interact ligand target protein develop two tool ishap grim align proteinligand complex interact pattern ishap base overlap interact pseudoatom use smooth gaussian function wherea grim util standard cliqu detect algorithm match interact pattern graph tool complementari enabl proteinligand complex align capit global local pattern similar new fingerprint companion align tool success use three scenario interactionbias align proteinligand complex ii postprocess dock pose accord known interact pattern particular target iii virtual screen bioisoster scaffold share similar interact pattern

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