Computational Investigation of Quantum Mechanical Tunnelling Effects on Hydrogen Transfer Reactions in Biological Systems Relevant to Nigerian Medicinal Plant Enzyme Targets

Quantum mechanical tunnelling contributes significantly to hydrogen transfer reactions catalysed by enzymes, and understanding tunnelling contributions to reaction rates is important for drug design targeting enzyme-catalysed processes. This dissertation presents an original computational investigation of quantum mechanical tunnelling effects on hydrogen and proton transfer reactions in the active sites of three enzymes identified as therapeutic targets in Nigerian medicinal plant pharmacology, specifically cyclooxygenase-2, xanthine oxidase, and acetylcholinesterase. Bioactive flavonoid compounds isolated from Combretum micranthum, Vitex doniana, and Ocimum gratissimum, plants used in traditional medicine across South West and South East Nigeria, were computationally studied as enzyme ligands. Quantum chemical calculations at the MP2 and CCSD levels with large basis sets were performed to characterise transition state geometries and potential energy surfaces for hydrogen transfer reactions in ligand-enzyme complexes modelled from crystallographic coordinates. Tunnelling coefficients were computed using the zero-curvature, small-curvature, and large-curvature tunnelling approximations implemented in Polyrate. Kinetic isotope effect calculations provided tunnelling benchmarks. QM-MM calculations using Gaussian and AMBER coupling incorporated protein environment effects on active site chemistry. Results reveal that tunnelling contributes between 40 and 85 percent of the observed proton transfer rate in cyclooxygenase-2-flavonoid complexes at physiological temperature, substantially larger than classical transition state theory predicts. Novel kinetic and thermodynamic descriptors correlating tunnelling contribution with inhibitory potency across the flavonoid series are derived. These represent original theoretical chemistry contributions relevant to enzyme-targeted drug discovery from Nigerian medicinal plant sources. Keywords: quantum tunnelling, hydrogen transfer, enzyme inhibition, computational chemistry, medicinal plants