Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors

Zheng Zhao; Philip E Bourne

doi:10.1021/acsptsci.3c00078

Rigid Scaffolds Are Promising for Designing Macrocyclic Kinase Inhibitors

ACS Pharmacol Transl Sci. 2023 Jul 7;6(8):1182-1191. doi: 10.1021/acsptsci.3c00078. eCollection 2023 Aug 11.

Authors

Zheng Zhao¹, Philip E Bourne¹

Affiliation

¹ School of Data Science and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22904, United States.

PMID: 37588756
PMCID: PMC10425998 (available on 2024-07-07)
DOI: 10.1021/acsptsci.3c00078

Abstract

Macrocyclic kinase inhibitors (MKIs) are gaining attention due to their favorable selectivity and potential to overcome drug resistance, yet they remain challenging to design because of their novel structures. To facilitate the design and discovery of MKIs, we investigate MKI rational design starting from initial acyclic compounds by performing microsecond-scale atomistic simulations for multiple MKIs, constructing an MKI database, and analyzing MKIs using hierarchical cluster analysis. Our studies demonstrate that the binding modes of MKIs are like those of their corresponding acyclic counterparts against the same kinase targets. Importantly, within the respective binding sites, the MKI scaffolds retain the same conformations as their corresponding acyclic counterparts, demonstrating the rigidity of scaffolds before and after molecular cyclization. The MKI database includes 641 nanomole-level MKIs from 56 human kinases elucidating the features of rigid scaffolds and the core structures of MKIs. Collectively these results and resources can facilitate MKI development.