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ReSCoSS: a flexible quantum chemistry workflow identifying relevant solution conformers of drug-like molecules

Abstract

Conformational equilibria are at the heart of drug design, yet their energetic description is often hampered by the insufficient accuracy of low-cost methods. Here we present a flexible and semi-automatic workflow based on quantum chemistry, ReSCoSS, designed to identify relevant conformers and predict their equilibria across different solvent environments in the Conductor-like Screening Model for Real Solvents (COSMO-RS) framework. We demonstrate the utility and accuracy of the workflow through conformational case studies on several drug-like molecules from literature where relevant conformations are known. We further show that including ReSCoSS conformers significantly improves COSMO-RS based predictions of physicochemical properties over single-conformation approaches. ReSCoSS has found broad adoption in the in-house drug discovery and development work streams and has contributed to establishing quantum-chemistry methods as a strategic pillar in ligand discovery.

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Acknowledgements

We thank colleagues from the global CADD group at NIBR-GDC and Grahame Woollam (TRD) for valuable feedback on applying ReSCoSS in projects. Wolfgang Zipfel and the NIBR NX Scientific Computing team are thanked for generous allocation of HPC resources. We thank Stefan Grimme for discussions around xTB, DFT functionals and solvation, Uwe Huniar for advice on Turbomole and Jens Reinisch and Michael Diedenhofen for helpful discussions about conformations and COSMO-RS.

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Correspondence to Anikó Udvarhelyi or Rainer Wilcken.

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Udvarhelyi, A., Rodde, S. & Wilcken, R. ReSCoSS: a flexible quantum chemistry workflow identifying relevant solution conformers of drug-like molecules. J Comput Aided Mol Des 35, 399–415 (2021). https://doi.org/10.1007/s10822-020-00337-7

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Keywords

  • Conformations
  • Quantum chemistry
  • GFN-xTB
  • COSMO-RS
  • logP
  • ReSCoSS