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High accuracy quantum-chemistry-based calculation and blind prediction of macroscopic pKa values in the context of the SAMPL6 challenge

Pracht, Philipp and Wilcken, Rainer and Udvarhelyi, Aniko and Rodde, Stephane and Grimme, Stefan (2018) High accuracy quantum-chemistry-based calculation and blind prediction of macroscopic pKa values in the context of the SAMPL6 challenge. Journal of Computer-Aided Molecular Design, 32 (10). pp. 1139-1149. ISSN 15734951

Abstract

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.

Item Type: Article
Keywords: DFT GFN-xTB Macroscopic pKa Quantum chemistry ReSCoSS SAMPL6
Date Deposited: 27 Dec 2018 00:45
Last Modified: 27 Dec 2018 00:45
URI: https://oak.novartis.com/id/eprint/36542

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