Abstract
Protein-protein interactions (PPIs) play a critical role in living cells and represent promising targets for the drug discovery and life sciences communities. However, lateral transmembrane PPIs are difficult targets for small-molecule inhibitor development given less structural information is known and fewer ligand discovery methods have been explored compared to soluble proteins. In this study, the interactions of the transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) were disrupted by pentamidine derivatives to curb the committed step of EBV infection. A pentamidine derivative 2 with a 7-atom di-amide linker had the best activity whilst switching the amide regiochemistry in the linker influenced membrane permeability and abolished anti TMD-5 activity. Molecular dynamics simulations were performed to understand the interaction between pentamidine derivatives and TMD-5, and to rationalise the observed structure-activity relationships. This study explicitly demonstrated that the interaction of small molecule with lipid should be considered alongside interaction with the protein target when designing small molecules targeting the PPIs of TMDs. In all, this study provides proof of concept for the rational design of small molecules targeting transmembrane PPIs.
Original language | English |
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Article number | 113210 |
Number of pages | 10 |
Journal | European Journal of Medicinal Chemistry |
Volume | 214 |
Early online date | 27 Jan 2021 |
DOIs | |
Publication status | Published - 15 Mar 2021 |
Bibliographical note
Funding Information:This work was supported by the National Natural Science Foundation of China [21602216, 21877106, 21807098]; Chinese Academy of Sciences (CAS) Pioneer Hundred Talents Program; the Young Talents Program of Chinese Academy of Agricultural Sciences; and the Royal Society-Newton Advanced Fellowship (NA170152). Computing time was supported by the Network and Computing Center, Changchun Institute of Applied Chemistry, CAS, the China Science and Technology Cloud, the National Supercomputing Center in Shenzhen and the Beijing Super Cloud Computing Center (BSCC).
Publisher Copyright:
© 2021 Elsevier Masson SAS
Keywords
- Protein-protein interactions
- Pentamidine analogues
- Latent membrane protein 1
- The fifth transmembrane domain (TMD-5)
- Epstein-barr virus
- Small molecule modulators
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry