A robust force field based method for calculating conformational energies of charged drug-like molecules
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A robust force field based method for calculating conformational energies of charged drug-like molecules. / Pøhlsgaard, Jacob; Harpsøe, Kasper; Jørgensen, Flemming Steen; Olsen, Lars.
In: Journal of Chemical Information and Modeling, Vol. 52, No. 2, 2012, p. 409-419.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A robust force field based method for calculating conformational energies of charged drug-like molecules
AU - Pøhlsgaard, Jacob
AU - Harpsøe, Kasper
AU - Jørgensen, Flemming Steen
AU - Olsen, Lars
PY - 2012
Y1 - 2012
N2 - The binding affinity of a drug like molecule depends among other things on the availability of the bioactive conformation. If the bioactive conformation has a significantly higher energy than the global minimum energy conformation, the molecule is unlikely to bind to its target. Determination of the global minimum energy conformation and calculation of conformational penalties of binding are prerequisites for prediction of reliable binding affinities. Here, we present a simple and computationally efficient procedure to estimate the global energy minimum for a wide variety of structurally diverse molecules, including polar and charged compounds. Identifying global energy minimum conformations of such compounds with force-field methods is problematic due to the exaggeration of intramolecular electrostatic interactions. We demonstrate that the global energy minimum conformations of zwitterionic compounds generated by conformational analysis with modified electrostatics are good approximations of the conformational distributions predicted by experimental data and in simulated annealing performed in explicit solvent.
AB - The binding affinity of a drug like molecule depends among other things on the availability of the bioactive conformation. If the bioactive conformation has a significantly higher energy than the global minimum energy conformation, the molecule is unlikely to bind to its target. Determination of the global minimum energy conformation and calculation of conformational penalties of binding are prerequisites for prediction of reliable binding affinities. Here, we present a simple and computationally efficient procedure to estimate the global energy minimum for a wide variety of structurally diverse molecules, including polar and charged compounds. Identifying global energy minimum conformations of such compounds with force-field methods is problematic due to the exaggeration of intramolecular electrostatic interactions. We demonstrate that the global energy minimum conformations of zwitterionic compounds generated by conformational analysis with modified electrostatics are good approximations of the conformational distributions predicted by experimental data and in simulated annealing performed in explicit solvent.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/ci200345f
DO - 10.1021/ci200345f
M3 - Journal article
C2 - 21985436
VL - 52
SP - 409
EP - 419
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
SN - 1549-9596
IS - 2
ER -
ID: 35359657