Unstable, metastable, or stable halogen bonding interaction involving negatively charged donors? A statistical and computational chemistry study.
The noncovalent halogen bonding could be attributed to the attraction between the positively charged σ-hole and a nucleophile. Quantum mechanics (QM) calculation indicated that the negatively charged organohalogens have no positively charged σ-hole on their molecular surface, leading to a postulation of repulsion between negatively charged organohalogens and nucleophiles in vacuum. However, PDB survey revealed that 24% of the ligands with halogen bonding geometry could be negatively charged. Moreover, 36% of ionizable drugs in CMC (Comprehensive Medicinal Chemistry) are possibly negatively charged at pH 7.0. QM energy scan showed that the negatively charged halogen bonding is probably metastable in vacuum. However, the QM calculated bonding energy turned negative in various solvents, suggesting that halogen bonding with negatively charged donors should be stable in reality. Indeed, QM/MM calculation on three crystal structures with negatively charged ligands revealed that the negatively charged halogen bonding was stable. Hence, we concluded that halogen bonding with negatively charged donors is unstable or metastable in vacuum but stable in protein environment, and possesses similar geometric and energetic characteristics as conventional halogen bonding. Therefore, negatively charged organohalogens are still effective halogen bonding donors for medicinal chemistry and other applications.
Drug Discovery and Design Center, Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
Zhuo
Z
Yang
Zhijian
Z
Xu
Yingtao
Y
Liu
Jinan
J
Wang
Jiye
J
Shi
Kaixian
K
Chen
Weiliang
W
Zhu
D006219:Halogens / Q000737:chemistry*; D006846:Hydrocarbons, Halogenated / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013816:Thermodynamics
D006219:Halogens; D006846:Hydrocarbons, Halogenated