PMID- 28657759
OWN - NLM
STAT- MEDLINE
DCOM- 20180504
LR  - 20191228
IS  - 1520-5207 (Electronic)
IS  - 1520-6106 (Print)
IS  - 1520-5207 (Linking)
VI  - 121
IP  - 28
DP  - 2017 Jul 20
TI  - Do Halogen-Hydrogen Bond Donor Interactions Dominate the Favorable Contribution 
      of Halogens to Ligand-Protein Binding?
PG  - 6813-6821
LID - 10.1021/acs.jpcb.7b04198 [doi]
AB  - Halogens are present in a significant number of drugs, contributing favorably to 
      ligand-protein binding. Currently, the contribution of halogens, most notably 
      chlorine and bromine, is largely attributed to halogen bonds involving favorable 
      interactions with hydrogen bond acceptors. However, we show that halogens acting 
      as hydrogen bond acceptors potentially make a more favorable contribution to 
      ligand binding than halogen bonds based on quantum mechanical calculations. In 
      addition, bioinformatics analysis of ligand-protein crystal structures shows the 
      presence of significant numbers of such interactions. It is shown that 
      interactions between halogens and hydrogen bond donors (HBDs) are dominated by 
      perpendicular C-X...HBD orientations. Notably, the orientation dependence of the 
      halogen-HBD (X-HBD) interactions is minimal over greater than 100 degrees  with favorable 
      interaction energies ranging from -2 to -14 kcal/mol. This contrasts halogen 
      bonds in that X-HBD interactions are substantially more favorable, being 
      comparable to canonical hydrogen bonds, with a smaller orientation dependence, 
      such that they make significant, favorable contributions to ligand-protein 
      binding and, therefore, should be actively considered during rational ligand 
      design.
FAU - Lin, Fang-Yu
AU  - Lin FY
AD  - Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School 
      of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
FAU - MacKerell, Alexander D Jr
AU  - MacKerell AD Jr
AUID- ORCID: 0000-0001-8287-6804
AD  - Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School 
      of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
LA  - eng
GR  - R01 GM070855/GM/NIGMS NIH HHS/United States
GR  - R01 GM072558/GM/NIGMS NIH HHS/United States
GR  - R44 GM109635/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170711
PL  - United States
TA  - J Phys Chem B
JT  - The journal of physical chemistry. B
JID - 101157530
RN  - 0 (Halogens)
RN  - 0 (Ligands)
RN  - 0 (Proteins)
SB  - IM
MH  - Databases, Protein
MH  - Halogens/chemistry/*metabolism
MH  - Hydrogen Bonding
MH  - *Ligands
MH  - Protein Structure, Tertiary
MH  - Proteins/chemistry/*metabolism
MH  - Quantum Theory
PMC - PMC5523114
COIS- The authors declare the following competing financial interest(s): A.D.M. is 
      co-founder and CSO of SilcsBio LLC.
EDAT- 2017/06/29 06:00
MHDA- 2018/05/05 06:00
PMCR- 2017/07/24
CRDT- 2017/06/29 06:00
PHST- 2017/06/29 06:00 [pubmed]
PHST- 2018/05/05 06:00 [medline]
PHST- 2017/06/29 06:00 [entrez]
PHST- 2017/07/24 00:00 [pmc-release]
AID - 10.1021/acs.jpcb.7b04198 [doi]
PST - ppublish
SO  - J Phys Chem B. 2017 Jul 20;121(28):6813-6821. doi: 10.1021/acs.jpcb.7b04198. Epub 
      2017 Jul 11.