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

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. [GRAPHICS] .

Automated summary

Conformational equilibria play a crucial role in drug design, but describing their energetics accurately can be challenging. A flexible and semi-automatic workflow called ReSCoSS, based on quantum chemistry, has been developed to identify relevant conformers and predict their equilibria in different solvent environments, improving predictions of physicochemical properties over single-conformation approaches in the COSMO-RS framework. This workflow has been widely adopted in drug discovery and development, establishing quantum chemistry methods as a strategic pillar in ligand discovery.