Energy windows for computed compound conformers: covering artefacts or truly large reorganization energies?. (16th January 2019)

• Record Type: Journal Article
• Authors: Foloppe, Nicolas; Chen, I-Jen
• Is Part Of: Future medicinal chemistry. Volume 11:Number 2(2019)
• Page Start: 97
• Page End: 118
• Publication Date: 2019-01-16
• Subjects: bioactive structure -- conformational analysis -- drug discovery -- intramolecular energy -- molecular modeling -- molecular recognition -- reorganization energy -- simulation -- virtual screening; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2018-0400
• Languages: English
• ISSNs: 1756-8919

Abstract

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 (ΔEw ), since only conformers within ΔEw are retained. However, ΔEw values in use appear unrealistically large. We analyze the factors pertaining to the conformer energetics and ΔEw . 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 ΔEw . Thus, this Perspective highlights the issues arising from low-energy conformers and suggests improvements via empirical or physics-based strategies. Graphical abstract: