Computational modelling of supramolecular human and animal structures: applications to enzymes relevant in comparative physiological studies

Odoemelam, C.S. ORCID: 0000-0002-9622-2075, 2023. Computational modelling of supramolecular human and animal structures: applications to enzymes relevant in comparative physiological studies. PhD, Nottingham Trent University.

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Currently, there is a need for improved drugs to treat diseases such as diabetes and cancer. This study used different computational methods to investigate a range of scientific problems that require rapid solutions to improve health and wellbeing. Ligand docking, in silico ADMET, protein-ligand binding affinity, density functional theory (DFT), and analytical techniques were applied to study the allosteric binding pocket of the GLP-1 receptor, the interactions between flavonoids and cytochrome P450s, the binding of phorbol diesters to the CYP19A1 enzyme and nuclear magnetic resonance (NMR) shielding. Findings from the study on ligand binding to the glucagon-like peptide-1 receptor GLP1-R) showed that the allosteric binding pocket of the GLP-1R is located near the transmembrane (TM) domain 6 of the receptor. This finding would enable the development of new allosteric modulators which can target the allosteric binding pocket of GLP-1R identified from this study. The next study which explored the binding of different ligands into cytochrome P450s showed that specific amino acid residues in the cytochrome P450s (CYP1A1 and CYP1B1) interact with different EROD flavonoids (Asp 313 and Phe 224 upon docking into CYP1A1 and Ala 330 upon docking into CYP1B1). The flavonoids isorhamnetin and pedalitin had the lowest binding energy upon docking into the crystal structures of 6DWM and 6IQ5. The results suggest the flavonoids isorhamnetin and pedalitin as potential precursors for natural productderived therapeutics. Additionally, the study also explored the interactions between phorbol diesters and CYP19A1. The results showed that the phorbol diesters had higher binding energy than commercial aromatase inhibitors. This suggests that phorbol diesters have the potential to modify the activity of the aromatase enzyme. A study investigating the lack of rotational invariance of some density functional theory (DFT) grids on DFT computed NMR spectra of a low vibrational frequency reaction showed that the lack of rotational invariance in some DFT grids does not impact DFT-calculated NMR spectra of low vibrational frequency reactions.

Item Type: Thesis
Creators: Odoemelam, C.S.
Wilson, P.Thesis
White, S.Thesis
Date: January 2023
Rights: The copyright in this work is held by the author and supervisors. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author.
Divisions: Schools > School of Animal, Rural and Environmental Sciences
Record created by: Linda Sullivan
Date Added: 26 Sep 2023 10:44
Last Modified: 26 Sep 2023 10:52

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