Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition

• Verfasst von: Jedwabny, Wiktoria [VerfasserIn]
• Verfasst von: Panecka-Hofman, Joanna [VerfasserIn]
• Verfasst von: Wade, Rebecca C. [VerfasserIn]
• Titel: Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition
• Verf.angabe: Wiktoria Jedwabny, Joanna Panecka-Hofman, Edyta Dyguda-Kazimierowicz, Rebecca C. Wade, W. Andrzej Sokalski
• E-Jahr: 2017
• Jahr: 07 July 2017
• Umfang: 14 S.
• Fussnoten: Published online: 07 July 2017 ; Gesehen am 20.08.2018
• Titel Quelle: Enthalten in: Journal of computer aided molecular design
• Ort Quelle: Dordrecht [u.a.] : Springer Science + Business Media B.V, 1987
• Jahr Quelle: 2017
• Band/Heft Quelle: 31(2017), 8, Seite 715-728
• ISSN Quelle: 1573-4951
• DOI: doi:10.1007/s10822-017-0035-4
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Ab initio
• Sach-SW: Binding affinity prediction
• Sach-SW: Interaction energy
• Sach-SW: Nonempirical model
• Sach-SW: Pteridine reductase 1
• Sach-SW: PTR1
• K10plus-PPN: 1580187420

Abstract

There is a need for improved and generally applicable scoring functions for fragment-based approaches to ligand design. Here, we evaluate the performance of a computationally efficient model for inhibitory activity estimation, which is composed only of multipole electrostatic energy and dispersion energy terms that approximate long-range ab initio quantum mechanical interaction energies. We find that computed energies correlate well with inhibitory activity for a compound series with varying substituents targeting two subpockets of the binding site of Trypanosoma brucei pteridine reductase 1. For one subpocket, we find that the model is more predictive for inhibitory activity than the ab initio interaction energy calculated at the MP2 level. Furthermore, the model is found to outperform a commonly used empirical scoring method. Finally, we show that the results for the two subpockets can be combined, which suggests that this simple nonempirical scoring function could be applied in fragment-based drug design.