Drug release by pH-responsive molecular tweezers: Atomistic details from molecular modeling
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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.
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