Energy windows for computed compound conformers: covering artefacts or truly large reorganization energies?

The generation of 3D conformers of small molecules underpins most computational drug discovery. Thus, the conformer quality is critical and depends on their energetics. A key parameter is the empirical conformational energy window (Delta E-w), since only conformers within Delta E-w are retained. However, Delta E-w values in use appear unrealistically large. We analyze the factors pertaining to the conformer energetics and Delta E-w. We argue that more attention must be focused on the problem of collapsed low-energy conformers. That is due to artificial intramolecular stabilization and occurs even with continuum solvation. Consequently, the conformational energy of extended bioactive structures is artefactually increased, which inflates Delta E-w. Thus, this Perspective highlights the issues arising from low-energy conformers and suggests improvements via empirical or physics-based strategies.