title: Drug release by pH-responsive molecular tweezers: atomistic details from molecular modeling.
abstract: pH-responsive molecular tweezers have been proposed as an approach for targeting drug-delivery to tumors, which tend to have a lower pH than normal cells. We performed a computational study of a pH-responsive molecular tweezer using ab initio quantum chemistry in the gas-phase and molecular dynamics (MD) simulations in solution. The binding free energy in solution was calculated using steered MD. We observe, in atomistic detail, the pH-induced conformational switch of the tweezer and the resulting release of the drug molecule. Even when the tweezer opens, the drug molecule remains near a hydrophobic arm of the molecular tweezer. Drug release cannot occur, it seems, unless the tweezer is in a hydrophobic environment with low pH.
authors: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada, L8S 4M1.
authors: Ahmed A K
authors: AA
authors: Mohammed
authors: Steven K
authors: SK
authors: Burger
authors: Paul W
authors: PW
authors: Ayers
mesh_terms: D016503:Drug Delivery Systems; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008846:Micromanipulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*; D011789:Quantum Theory
chemical_list: D011725:Pyridines
keywords: density functional theory; drug release; drug targeting; molecular switching; molecular tweezers; pH-responsive molecules; steered molecular dynamics