Torsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independence

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dc.contributor.authorWei, Wanlei
dc.contributor.authorChampion, Candide
dc.contributor.authorBarigye, Stephen J.
dc.contributor.authorLabute, Paul
dc.contributor.authorMoitessier, Nicolas
dc.date.accessioned2023-02-09T21:18:59Z
dc.date.available2023-02-09T21:18:59Z
dc.date.issued2019
dc.description.abstractBiaryl molecules are ubiquitous pharmacophores found in natural products and pharmaceuticals. In spite of this, existing molecular mechanics force fields are unable to accurately reproduce their torsional energy profiles, except for a few well-parametrized cases. This effectively limits the ability of structure-based drug design methods to correctly identify hits involving biaryls with confidence (e.g., during virtual screening, employing docking and/or molecular dynamics simulations). Continuing in our endeavor to quantify organic chemistry principles, we showed that the torsional energy profile of biaryl compounds could be computed on-the-fly based on the electron richness/deficiency of the aromatic rings. This method, called H-TEQ 4.0, was developed using a set of 131 biaryls. It was subsequently validated on a separate set of 100 diverse biaryls, including multisubstituted, bicyclic and tricyclic druglike molecules, and produced an average root-mean-square error (RMSE) of 0.95 kcal·mol–1. For comparison, GAFF2 produced an RMSE of 3.88 kcal·mol–1, owing to problems associated with the transferability of torsion parameters. The success of H-TEQ 4.0 provided further evidence that force fields could transition to become atom-type independent, providing that the correct chemical principles are used. Overall, this method solved the problem of transferability of biaryl torsion parameters, while simultaneously improving the overall accuracy of the force field.en_US
dc.identifier.citationWei, W., Champion, C., Liu, Z., Barigye, S. J., Labute, P., & Moitessier, N. (2019). Torsional energy barriers of biaryls could be predicted by electron richness/deficiency of aromatic rings; advancement of molecular mechanics toward atom-type independence. Journal of chemical information and modeling, 59(11), 4764-4777.https://doi.org/10.1021/acs.jcim.9b00585en_US
dc.identifier.urihttps://nru.uncst.go.ug/handle/123456789/7734
dc.language.isoenen_US
dc.publisherJournal of chemical information and modelingen_US
dc.subjectBiarylsen_US
dc.subjectTorsional Energyen_US
dc.subjectaromatic ringsen_US
dc.titleTorsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independenceen_US
dc.typeArticleen_US
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