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

Publication: Research - peer-reviewJournal article

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.
Original languageEnglish
JournalJournal of Chemical Information and Modeling
Issue number2
Pages (from-to)409-419
StatePublished - 2012

ID: 35359657