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Title: Developments and applications in computer-aided drug discovery
Author: Ibrahim, Mahmoud Arafat Abd el-hamid
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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Noncovalent interactions are of great importance in studies on crystal design and drug discovery. One such noncovalent interaction, halogen bonding, is present between a covalently bound halogen atom and a Lewis base. A halogen bond is a directional interaction caused by the anisotropic distribution of charge on a halogen atom X covalently bound to A, which in turn forms a positive region called σ-hole on the A–X axis. Utilization of halogen bonds in lead optimization have been rarely considered in drug discovery until recently and yet more than 50% of the drug candidates are halogenated. To date, the halogen bond has not been subjected to practical molecular mechanical-molecular dynamics (MM-MD) study, where this noncovalent interaction cannot be described by conventional force fields because they do not account for the anisotropic distribution of the charge density on the halogen atoms. This problem was solved by the author and, for the first time, an extra-point of positive charge was used to represent the σ-hole on the halogen atom. This approach is called positive extra-point (PEP) approach. Interestingly, it was found that the performance of the PEP approach in describing halogen bond was better than the semiempirical methods including the recent halogen-bond corrected PM6 (PM6-DH2X) method. The PEP approach also gave promising results in describing other noncovalent halogen interactions, such as C–X···H and C–X···π-systems. The PEP resulted in an improvement in the accuracy of the electrostatic-potential derived charges of halogen-containing molecules, giving in turn better dipole moments and solvation free energies compared to high-level quantum mechanical and experimental data.With the aid of our PEP approach, the first MM-molecular dynamics (MM-MD) study of inhibitors that form a halogen bond with a receptor was performed for tetrahalobenzotriazole inhibitors complexed to cyclin-dependent protein kinase (CDK2). When the PEP approach was used, the calculated MM-generalized Born surface area (MM-GBSA)//MM-MD binding energies for halobenzimidazole and halobenzotriazole inhibitors complexed with protein kinase CK2 were found to correlate well with the corresponding experimental data, with correlation coefficients R2 of greater than 0.90. The nature and strength of halogen bonding in halo molecule···Lewis base complexes were studied in terms of molecular mechanics using our PEP approach. The contributions of the σ-hole (i.e., positively charged extra-point) and the halogen atom to the strength of this noncovalent interaction were clarified using the atomic parameter contribution to the molecular interaction approach. The molecular mechanical results revealed that the halogen bond is electrostatic and van der Waals in nature. The strength of the halogen bond increases with increasing the magnitude of the extra-point charge. The van der Waals interaction’s contribution to the halogen bond strength is most favorable in chloro complexes, whereas the electrostatic interaction is dominant in iodo complexes.The failure of the PM6 semiempirical method in describing noncovalent halogen interactions —not only halogen bonds, but also hydrogen bonds involving halogen atoms— was reported and corrected by the introduction of a second and third generation of noncovalent halogen interactions correction. The developed correction yielded promising results for the four examined noncovalent halogen interactions, namely: C–X···O, C–X···N, C–X···π-system, and C–X···H interactions.
Supervisor: Burton, Neil Sponsor: Egyptian Ministry of Higher Education and Scientific Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Computational Chemistry ; Quantum Mechanics ; Molecular Mechancis ; Molecular Dynamics ; Drug Discovery ; Noncovalent Interaction ; Halogen Bond ; Sigma-Hole ; PEP Approach ; APCtMI Approach ; CKD2 Protein ; CK2 Protein