Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 32, Issue 10, Pages 1139-1149Publisher
SPRINGER
DOI: 10.1007/s10822-018-0145-7
Keywords
SAMPL6; Macroscopic pKa; Quantum chemistry; DFT; GFN-xTB; ReSCoSS
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Funding
- German Research Foundation (DFG) through a Leibniz prize
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Recent advances in the development of low-cost quantum chemical methods have made the prediction of conformational preferences and physicochemical properties of medium-sized drug-like molecules routinely feasible, with significant potential to advance drug discovery. In the context of the SAMPL6 challenge, macroscopic pKa values were blindly predicted for a set of 24 of such molecules. In this paper we present two similar quantum chemical based approaches based on the high accuracy calculation of standard reaction free energies and the subsequent determination of those pKa values via a linear free energy relationship. Both approaches use extensive conformational sampling and apply hybrid and double-hybrid density functional theory with continuum solvation to calculate free energies. The blindly calculated macroscopic pKa values were in excellent agreement with the experiment.
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