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.
| Original language | English |
|---|---|
| Pages (from-to) | 1317-1328 |
| Number of pages | 12 |
| Journal | Journal of chemical information and modeling |
| Volume | 60 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 23 Mar 2020 |
Funding
We thank Cedric Koolen, M.Sc. and Joep Wals, B.Sc. for their contribution to this work. Furthermore, we thank Daniela Rodrigues Silva, M.Sc. and Dr. Tanja Sergeieva for their insightful discussions. We thank the Netherlands Organization for Scientific Research (NWO) for financial support and L.d.A.S. for the scholarship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Grant 88881.190191/2018-01). G.P. would like to acknowledge financial support from the Hungarian Scientific Research Fund (OTKA) K111862.
| Funders | Funder number |
|---|---|
| Coordenação de Aperfeiçoamento de Pessoal de Nível Superior | 88881.190191/2018-01 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Hungarian Scientific Research Fund | K111862 |