Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design

Beekman, Andrew M. ORCID: https://orcid.org/0000-0002-3056-6406, Cominetti, Marco M. D., Walpole, Samuel J., Prabhu, Saurabh, O'Connell, Maria A. ORCID: https://orcid.org/0000-0002-0267-0951, Angulo Alvarez, Jesus ORCID: https://orcid.org/0000-0001-7250-5639 and Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 (2019) Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design. Chemical Science, 10 (16). pp. 4502-4508. ISSN 2041-6520

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Abstract

The development of protein-protein interaction (PPI) inhibitors with therapeutic value is of increasing importance as the first clinical agent has now been approved, but PPIs remain difficult targets for the development of small molecule ligands. This article describes a highly efficient approach to the development of inhibitors of the p53/hDMX or hDM2 interaction that involves the design of small molecules in silico based upon a peptide/protein structure. The process for molecule design, starting from a virtual library of just over 1200 fragments, led to the eventual synthesis of twenty compounds, of which ten bound to either hDM2, hDMX or both in vitro binding assays. This 50% success rate is extremely efficient compared to traditional high throughput screening. The identification of two selective hDMX inhibitors from twenty compounds highlights this efficiency as, to date, only two other hDMX-selective agents exist in the literature. Preliminary biological studies show that 20% of the compounds identified have cellular activity and activate downstream pathways associated with p53 activation.

Item Type:	Article
Additional Information:	Correction at 10.1039/c9sc90088h
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry (former - to 2024) Faculty of Science
UEA Research Groups:	Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) Faculty of Science > Research Groups > Molecular and Tissue Pharmacology Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
Depositing User:	LivePure Connector
Date Deposited:	12 Mar 2019 14:30
Last Modified:	03 Dec 2024 01:24
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70209
DOI:	10.1039/C9SC00059C

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