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Chiral Graphs: Reduced Representations of Ligand Scaffolds for Stereoselective Biomolecular Recognition, Drug Design, and Enhanced Exploration of Chemical Structure Space
Author(s) -
Mikhael Simoun,
Abrol Ravinder
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800761
Subject(s) - stereocenter , stereoselectivity , chemical space , ligand (biochemistry) , chemistry , stereochemistry , combinatorial chemistry , drug discovery , docking (animal) , chirality (physics) , topology (electrical circuits) , computational biology , enantioselective synthesis , mathematics , physics , biology , receptor , biochemistry , chiral perturbation theory , medicine , nursing , combinatorics , catalysis , pion , particle physics , nambu–jona lasinio model
Rational structure‐based drug design relies on a detailed, atomic‐level understanding of protein–ligand interactions. The chiral nature of drug binding sites in proteins has led to the discovery of predominantly chiral drugs. A mechanistic understanding of stereoselectivity (which governs how one stereoisomer of a drug might bind stronger than the others to a protein) depends on the topology of stereocenters in the chiral molecule. Chiral graphs and reduced chiral graphs , introduced here, are new topological representations of chiral ligands using graph theory, to facilitate a detailed understanding of chiral recognition of ligands/drugs by proteins. These representations are demonstrated by application to all ≈14 000+ chiral ligands in the Protein Data Bank (PDB), which will facilitate an understanding of protein–ligand stereoselectivity mechanisms. Ligand modifications during drug development can be easily incorporated into these chiral graphs. In addition, these chiral graphs present an efficient tool for a deep dive into the enormous chemical structure space to enable sampling of unexplored structural scaffolds.