I completed an undergraduate Degree in Computational Chemistry in Trinity College Dublin in 2001 and commenced a Ph.D.
I am interested in studying Benign Prostatic Hyperplasia (BPH), a progressive condition, which is characterised by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra.1 The a1A adrenoceptor (A1AA) has recently received much attention as antagonist blockade of contraction of human prostate tissue has been found to correlate with affinity for the A1A subtype.
The connection of 2 phenyl groups by a group containing polar atoms (1) NH, (2) CO, (3) SO2 and (4) CH2 (Figure 1) for comparison were considered for both the bis-2-iminoimidazolidinium (A) and bis-guanidinium (B) as possible antagonists in the treatment of BPH.2 These drugs along with others used clinically were further investigated computationally. Conformational analysis was performed to determine viable conformers, followed by structural optimisations at the DFT level of B3LYP/6-31G* with Onsager solvation model. A proton affinity and pKa study followed by a subsequent fit to a pharmacophore model3 was examined to determine possible conformations of each drug in the binding site.
Our knowledge of 3D structures of membrane proteins such as G protein coupled receptors (GPCR.s) is limited, and no crystal structure is available for the A1AA. This problem was approached, by combining 3D model building of receptor structure4 and computational simulation of receptor dynamics. A homology model was built based on the bovine rhodopsin structure.
The binding of high affinity ligands to this model was examined through docking. We aim to firstly study the known agonist binding site, and then examine possible antagonist binding sites as determined with our protein model. Extra force field parameters are being added for more accurate molecular dynamics (MD) simulations on the drug-like molecules. MD will then be performed on the docked complexes using a bilayer mimic.
References: 1 Matyus, P., Horvath, K., Medicinal Research Reviews, 1997, 17 6 523-535 2 Dardonville, C.,Goya, P., Rozas,I., Alsasua, A., Martin, I., Borrego, J. Bioorganic & Medicinal Chemistry, 2000, 8 1567-1577 3 Bremner, J. B. Coban, B., Griffith, R., Journal of Computer-aided Molecular Design, 1996, 10 545-557 4 Sali, A., Blundell, T., J. Mol.Biol, 1993, 234 779-815