90009438

open access

Accepted Manuscript

Protein-ligand binding affinity prediction of cyclin-dependent kinase-2 inhibitors by dynamically averaged fragment molecular orbital-based interaction energy

English (英語)

Journal of Computational Chemistry

43(20)

1362-1371

Wiley

2022-07-30

2023-08-01

Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein–ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein–ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R² = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of −1 was added, the DA FMO-based scheme with the dispersion energies still achieved R² = 0.99, whereas R² decreased to 0.32 employing all the energy terms of PIEDA.

pair interaction energy decomposition analysis

学術雑誌論文

This is the peer reviewed version of the following article: [Takaba, K., Watanabe, C., Tokuhisa, A., Akinaga, Y., Ma, B., Kanada, R., Araki, M., Okuno, Y., Kawashima, Y., Moriwaki, H., Kawashita, N., Honma, T., Fukuzawa, K., Tanaka, S., J. Comput. Chem. 2022, 43(20), 1362.], which has been published in final form at https://doi.org/10.1002/jcc.26940. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.