Abstract
This thesis represents theoretical investigations of the selective hydrolysis of ester and phosphoester bonds catalyzed by metalloenzymes and their synthetic analogues. Additionally, studies regarding interactions of small molecules related to prostate cancer and Alzheimer’s disease with their receptors are included. Specifically, the following four projects are discussed: (1) ester hydrolysis by neprilysin (NEP, a metalloprotease) and cutinase-like enzyme (CLE, a serine protease), (2) phosphoester hydrolysis by glycerophosphodiesterase (GpdQ, a dinuclear metallophosphatase) and metal-cyclen (M-C) complexes, (3) inhibition of prostate specific membrane antigen (PSMA) for boron neutron capture therapy (BNCT) and (4) oxidation of Alzheimer Aβ1-40 monomer by a metal complex. The first project concerns the degradation of a main plastic pollutant polyethylene terephthalate (PET) by two distinct proteases, NEP and CLE. Our results suggested that the Lewis acid and nucleophile activations provided by the Zn metal center of NEP are more effective than the hydrogen bonding interactions provided by the catalytic triad of CLE in the mechanism. The second project is related to the hydrolysis of chemically distinct phosphoester bonds by a Fe-Zn core containing promiscuous enzyme GpdQ and a mononuclear organometallic metal-cyclen complex. Our studies demonstrated that GpdQ utilizes different hydrolytic mechanisms on the basis of the chemical nature of its substrates. On the other hand, for M-C complexes, the divalent metal (Zn, Cu and Co) ions were found to be more efficient than their tetravalent (Ce, Zr and Ti) counterparts. The third project deals with the interactions of several distinct boron-containing urea-based small molecules with PSMA. The inhibitor with carborane ball was identified as the most promising molecule for BNCT due to its high boron density and strong binding affinity. Finally, the last project is regarding the interactions of a Re complex - [Re(CO)3(dppz)(Py)]+ (dppz = dipyrido[3,2-a:2’,3’-c]phenazine; Py = pyridine) with the Alzheimer Aβ1-40 monomer. This molecule can oxidize Aβ1-40 and modulate its aggregation.