3sym

Publication Abstract from PubMed

Glycogen phosphorylase is a molecular target for the design of potential hypoglycaemic agents. Structure based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme's cofactor, PLP, thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(beta-D-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH(2) OH glucopyranose derivative. Both ligands were found to be low muM inhibitors with K(i) values of 7.9 and 27.1 muM, respectively. X-ray crystallography revealed that the 3'-CH(2) OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared to GlcFU. However it is 3.4 times less potent. To elucidate this discovery, docking followed by post-docking Quantum Mechanics/Molecular Mechanics - Poisson Boltzmann Surface Area (QM/MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desolvation energy cost for binding of the 3'-CH(2) OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing post-docking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization is therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant. (c) 2012 John Wiley & Sons A/S.

3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.,Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D Chem Biol Drug Des. 2012 Feb 2. doi: 10.1111/j.1747-0285.2012.01349.x. PMID:22296957^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.