Premium
3′‐Axial CH 2 OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why
Author(s) -
Manta Stella,
Xipnitou Andromachi,
Kiritsis Christos,
Kantsadi Anastassia L.,
Hayes Joseph M.,
Skamnaki Vicky T.,
Lamprakis Christos,
Kontou Maria,
Zoumpoulakis Panagiotis,
Zographos Spyridon E.,
Leonidas Demetres D.,
Komiotis Dimitri
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2012.01349.x
Subject(s) - chemistry , qm/mm , glycogen phosphorylase , docking (animal) , substituent , stereochemistry , molecular mechanics , computational chemistry , molecular dynamics , enzyme , biochemistry , medicine , nursing
Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic 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, pyridoxal 5′‐phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1‐( β ‐ d ‐glucopyranosyl)5‐fluorouracil (GlcFU) and its 3′‐CH 2 OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with K i values of 7.9 and 27.1 μ m , respectively. X‐ray crystallography revealed that the 3′‐CH 2 OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP γ‐phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking 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 postdocking calculations employing a more accurate solvation model and the QM/MM‐PBSA methodology in lead optimization are therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant.