الفهرس 
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Abstract
Halogen bond has recently entered the arena of reliable and valuable non-covalent interactions for the construction of supramolecular complexes. However, halogen bond (XB) has been recognized as an effective tool in rational drug design, role and nature of halogen bond are still a source of debate. In the current thesis, the halogen bond was studied from molecular and quantum mechanical perspectives. from molecular mechanical perspective, the role of halogen bond in drug-receptor complexes was investigated to gain a better molecular and energetic insight of drug candidates, which form halogen bonds. Halo-derivatives of benzimidazole in complex with Casein kinase 2 (CK2) protein was investigated as a case study. σ-Hole on the halogen atom was introduced in molecular mechanics with the help of positive-extra-point (PEP) approach, in which an extra point of positive charge was used to mimic the σ-hole. The halogenated-inhibitor∙∙∙CK2 complexes were minimized using ff14SB force field implemented in AMBER14 package. The binding energies (∆Gbinding) of the studied complexes were calculated using molecular mechanic Generalized Born and surface area continuum solvation approach (MM-GBSA) based on the molecular mechanically minimized structures. The used methodology to calculate the binding energies of inhibitors with CK2 protein was examined, giving a correlation coefficient (R2) value of 0.97 with respect to the reported experimental data. Atomic parameter contribution to molecular interaction (i.e. the contribution of halogen’s electrostatic and van der Waals parameters) was estimated using Atomic Parameter Contribution to Molecular Interaction (APCtMI) approach. APCtMI results revealed that halogen’s negative charge has no significant contribution to the total MM-GBSA binding energy. Furthermore, van der Waals interactions have a significant impact on the halogenated-inhibitors∙∙∙receptor binding energy. The results were further assessed with the help of halogen bond test (–σ-hole test) at AMBER-molecular mechanical (MM) level. These results should further the role of halogens for the purpose of drug discovery and development.
Moreover, from quantum mechanical perspective, the halogen bond nature was investigated with the integration of Point-of-Charge (PoC) approach. PoC approach was implemented instead of the Lewis acid/base to rule out the noncovalent interactions rather than the electrostatic interaction among the halomolecule and the Lewis base. The main aims of this part of study were to establish a list of characteristics for the halogen bond, to address important features of the halogen bond such as polarization effect, and to solve halogen bond-related scientific dogmas. To reveal halogen bond characteristics, quantum mechanical calculations were carried out on a dozen of halogen-containing molecules including halobenzene, halomethane and hydrogen halide (C6H5X, CH3X and HX, where X= I, Br, Cl and F). The geometry of the studied molecules was firstly optimized at MP2 level of theory using aug-cc-pVDZ basis set for all studied atoms with the exception of bromine and iodine atoms. Bromine and iodine atoms were treated with aug-cc-pVDZ-PP basis set. The importance of polarization in the halogen bond interaction was estimated. The effect of halogen•••PoC distance on halogen bond strength was investigated in the range from 2.5 Å to 6.0 Å. The effect of A-X•••PoC angle (θ) was also examined in the range from 90˚ to 180˚. The halogen bond strength was estimated in terms of molecular stabilization energy. The effect of solvent on the molecular stabilization energy was investigated. Moreover, contribution of electron correlation to molecular stabilization energy was evaluated. Natural bonding orbital (NBO) calculations were established in order to study the correlation between the halogen bond strength and the change (∆) in highest occupied molecular orbital (HOMO) energy (∆EHOMO), p-orbital contribution to hybridization of A-X bond and p-electron configuration and natural charge of the halogen atom. Halogen bond test (σn-hole test) was performed to examine the ability of a halomolecule to form a halogen bond. A number of fundamental physical terms including σ-node, –σ-hole and +σ-hole interactions were introduced to describe the halogen’s interactions. To validate the PoC approach, all PoC-based results were compared to those of halomolecule•••Lewis base/acid complexes. In the latter calculation, fluorine and lithium ions were used instead of the negative and positive PoC, respectively.
from the obtained quantum mechanics results, halogen bond is considered as an electrostatic interaction and the polarization has the major role in the formation of halogen•••Lewis acid/base interaction. Moreover, the existence of σ-hole is not a guarantee for the halomolecule to form a halogen bond with a Lewis base. As well, the halomolecule has the ability to interact with both Lewis base and acid at A X•••angle of ≈180°, termed “–σ hole interaction” and “+σ hole interaction”, respectively. It was found that increasing PoC negative charge led to an increase in σ-hole size and, in turn, the halogen bond strength in contrast with increasing PoC positive charge. According to NBO results, the EHOMO was inversely proportional to the magnitude of σ-hole. As well, the natural charge of the halogen atom decreased as the σ-hole size decreases. p-electron configuration of the halogen atom was increased as the halogen bond strength decreases and p-orbital contribution to A-X bond hybridization was directly correlated to the σ-hole size. In aqueous phase, the negatively charged PoC was led to a molecular destabilization for most studied halomolecules; in contrast, positively charged PoC was led to a molecular stabilization. All calculations were performed using High-Performance Computer (HPC) located at CompChem Lab, Minia University, and supported by the Science and Technology Development Fund, STDF, Egypt, Grant No. 5480.