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Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation

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Abstract

Accurate calculation of relative tautomer energies in different environments is a prerequisite to many parameters of relevance in drug discovery. This work provides a thorough benchmark of the semiempirical methods AM1, PM3 and GFN2-xTB, the force-field OPLS4, Hartree–Fock and HF-3c, the density functionals PBEh-3c, B97-3c, r2SCAN-3c, PBE, PBE0, TPSS, r2SCAN, ω-B97X-V, M06-2X, B3LYP, B2PLYP, and second-order perturbation theory MP2 versus the gold-standard coupled-cluster DLPNO-CCSD(T) using the def2-QZVPP basis set. The outperforming method identified is M06-2X, whereas r2SCAN-3c is the best-perfoming one in the set of cost-optimized methods. Application of the two methods on a challenging subset from the SAMPL2 challenge provides evidence that deviations from experiment are caused by deficiencies of current continuum solvation methods.

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The datasets supporting the conclusions of this article are included within the article and its additional files.

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Authors and Affiliations

  1. Computational Molecular Design, Bayer AG, Aprather Weg 18a, 42096, Wuppertal, Germany

    Andreas H. Göller

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  1. Andreas H. Göller
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AG developed the concept, did all calculations and wrote the manuscript.

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Correspondence to Andreas H. Göller.

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Supplementary Information

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10822_2022_480_MOESM1_ESM.sdf

Additional File 2: Text file with the 3D-coordinates of 65 tautomers of the 13 molecules of dataset 1 in SDF format. (Text) (SDF 135 kb)

10822_2022_480_MOESM2_ESM.sdf

Additional File 3: Text file with the 3D-coordinates of 24 tautomers of the 11 molecules of dataset 2 in SDF format. (Text) (SDF 24 kb)

10822_2022_480_MOESM3_ESM.docx

Additional File 1: Complete set of plots of the tautomer states and ΔE histograms for all molecules in all methods and additional tables with tautomer energies for dataset 2. (PDF) (DOCX 2912 kb)

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Göller, A.H. Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation. J Comput Aided Mol Des 36, 805–824 (2022). https://doi.org/10.1007/s10822-022-00480-3

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