Perspectives of Halogen Bonding Description in Scoring Functions and QSAR/QSPR: Substituent Effects in Aromatic Core

Abstract

Halogen bonding (XB) is a new promising interaction pattern in medicinal chemistry. It has predominantly electrostatic nature - high electrostatic potential anisotropy. However to fully unleash the potential of XB in rational drug design fast and robust empirical methods of XB description should be developed. Current approaches rely heavily on ab initio calculation for each molecule studied. Thus fast prediction of electrostatic parameters for description of XB for arbitrary organic molecules is of paramount importance to promptly establish QSAR/QSPR, virtual screening and molecular docking pipelines suitable for today's agile development requirements. The two most promising approaches to describe anisotropic electrostatic models - the extra point (EP) charge model and the multipole expansion (ME) model - were studied on their ability (1) to describe ab initio molecular electrostatic potential (MEP) and (2) to produce parameters that can be predicted for each molecule empirically rather than estimated via ab initio calculations. The reference ab initio MEP was calculated for a set of 730 substituted halobenzenes. Parameters for anisotropic electrostatics of both empirical models (EP and ME) studied were extracted from ab initio MEP. The FreeWilson and Hansch type QSPR models relating XB parameters with aromatic substituents were built and analyzed, providing the guidelines for further development.

Computer Modeling of Halogen Bonds and Other σ-Hole Interactions

“…We suggested that a distance between 1.2 and 1.5 Å would be reasonable. A recent study proposed 1.33 Å, which agrees with the previous findings. Slightly higher equilibrium distances were used in OPLS-AA, i.e., 1.6 Å for the ESH of chlorine and bromine and 1.8 Å for the ESH of iodine.…”

“…205,206 It was shown, however, that the point electric quadrupole sufficiently represents the electrostatic situation on a covalently bonded halogen 207 and that excluding the dipole from the expansion increases the certainty of the quadrupole by about one order of magnitude. 204 Torii and Yoshida 205 fitted the atomic point charges of an entire molecule with a quadrupole moment located only on the halogen. They found that the zz component of a traceless quadrupole (where the z-axis coincides with the R-X covalent bond) is insensitive to aromatic substituents, and the substitution effect is rather manifested by the variations of the atomic point charges.…”

“…They found that the zz component of a traceless quadrupole (where the z axis coincides with the R−X covalent bond) is insensitive to aromatic substituents, and the substitution effect is rather manifested by the variations of the atomic point charges. Titov et al 204 compared the performance of the off-center charge model and the multipole expansion in reproducing QM-based molecular electrostatic potential. Their major finding was that both models performed equally well when the nonhalogen part of the molecule was described in the same way.…”

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

“…However, para-substituted derivatives break the trend, suggesting a modification on the binding mechanism resulting from the change in halogen position, which would not be properly described by the scoring function. In general, the description of halogen bonding is not consistently described in scoring functions requiring in-depth study [34]. Meta-substituted compounds show a similar binding mechanism, H-π interactions being the most prevalent.…”

Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay

“…Consequently, the imperfection in dealing with halogen bonding influences the accuracy of scoring function to a great extent for drug repositioning as well. There are several docking scoring functions emerged to fill the gaps in this area 24 25 26 . Recently, our laboratory developed a docking software, namely D 3 DOCKxb, which showed good performance in a docking power evaluation among test sets with halogen bonding interactions due to its reliable halogen bond scoring function 27 28 .…”