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Halogen Bonds in Ligand-Protein Systems: Molecular Orbital Theory for Drug Design.

ABSTRACT: Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn-Sham molecular orbital theory together with energy decomposition analysis, reveal that donor-acceptor interactions and steric repulsion between the occupied orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.

SUBMITTER: Margiotta E 

PROVIDER: S-EPMC7093837 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Halogen Bonds in Ligand-Protein Systems: Molecular Orbital Theory for Drug Design.

Margiotta Enrico E   van der Lubbe Stephanie C C SCC   de Azevedo Santos Lucas L   Paragi Gabor G   Moro Stefano S   Bickelhaupt F Matthias FM   Fonseca Guerra Célia C  

Journal of chemical information and modeling 20200213 3

Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the s  ...[more]

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