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Extension of an Atom-Atom Dispersion Function to Halogen Bonds and Its Use for Rational Design of Drugs and Biocatalysts.

ABSTRACT: A dispersion function D_as in the form of a damped atom-atom asymptotic expansion fitted to ab initio dispersion energies from symmetry-adapted perturbation theory was improved and extended to systems containing heavier halogen atoms. To illustrate its performance, the revised D_as function was implemented in the multipole first-order electrostatic and second-order dispersion (MED) scoring model. The extension has allowed applications to a much larger set of biocomplexes than it was possible with the original D_as. A reasonable correlation between MED and experimentally determined inhibitory activities was achieved in a number of test cases, including structures featuring nonphysically shortened intermonomer distances, which constitute a particular challenge for binding strength predictions. Since the MED model is also computationally efficient, it can be used for reliable and rapid assessment of the ligand affinity or multidimensional scanning of amino acid side-chain conformations in the process of rational design of novel drugs or biocatalysts.

SUBMITTER: Jedwabny W

PROVIDER: S-EPMC8028329 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

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2020-03-20 | PXD005934 | Pride

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