A robust force field based method for calculating conformational energies of charged drug-like molecules

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 - 2012/2/27

Y1 - 2012/2/27

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, then the molecule is unlikely to bind to its target. Determination of the global minimum energy conformation and calculation of conformational penalties of binding is a prerequisite 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 with molecular dynamics performed in explicit solvent. Finally the method is used to calculate conformational penalties for zwitterionic GluA2 agonists and to filter false positives from a docking study.

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, then the molecule is unlikely to bind to its target. Determination of the global minimum energy conformation and calculation of conformational penalties of binding is a prerequisite 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 with molecular dynamics performed in explicit solvent. Finally the method is used to calculate conformational penalties for zwitterionic GluA2 agonists and to filter false positives from a docking study.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/ci200345f

DO - 10.1021/ci200345f

M3 - Journal article

C2 - 21985436

SN - 1549-9596

VL - 52

SP - 409

EP - 419

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

IS - 2

ER -