Identification of new ClpC1-NTD binders for Mycobacterium tuberculosis drug development
MtbClpC1 is a promising drug target against tuberculosis. Recent studies have shown that several natural product antibiotics targeting the unfoldase N-terminal domain can impair MtbClpC1 function resulting in cell death. While the pharmacological properties of these natural product antibiotics prevent their use in the clinic, similar molecules binding to the same binding pockets can result in new drugs against Mtb. Here we demonstrate that we successfully used in silico screening to identify new ClpC1 N-terminal domain binders with micromolar affinity from a small compound library. In addition, we experimentally demonstrate that the new compounds bind to the same pockets used by the natural product antibiotics and inhibit ClpC1 function.
Authors
- Carine van Heijenoort (ORCID: https://orcid.org/0000-0002-2839-1037)
- Sonia Vega (ORCID: https://orcid.org/0000-0002-1232-6310)
- Eric J. Rubin (ORCID: https://orcid.org/0000-0001-5120-962X)
- Sandra Beaupierre
- Ian D. Wolf (ORCID: https://orcid.org/0000-0002-2455-6148)
- Catherine Guillou (ORCID: https://orcid.org/0000-0003-0693-0703)
- Tatos Akopian
- Diego F. Gauto (ORCID: https://orcid.org/0000-0003-3757-2830)
- Hugo Fraga (ORCID: https://orcid.org/0000-0001-7677-4086)
- Olga Krandor
- Katharina Weinhäupl (ORCID: https://orcid.org/0000-0002-9552-9876)
- Sandy Desrat (ORCID: https://orcid.org/0000-0002-6544-9242)
- Adrián Velázquez‐Campoy (ORCID: https://orcid.org/0000-0001-5702-4538)
- Nelly Morellet
- Olga Abián (ORCID: https://orcid.org/0000-0001-5664-1729)
- Louis Meuret
- Fanny Roussy
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut de Chimie des Substances Naturelles (FR)
- Harvard University (US)
- Universidade do Porto (PT)
- Universidad de Zaragoza (ES)
- Centro de Investigación Biomédica en Red (ES)
- Institute of Mechanical Engineering and Industrial Mangement (PT)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Instituto de Investigación Sanitaria Aragón (ES)
- Institut de Biologie Structurale (FR)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- INFRANALYTICS
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1038/s41598-025-87535-1
- Citations
- 3
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 4.51
Funders
- European Commission
- Ministerio de Ciencia e Innovación
- European Regional Development Fund
- Agencia Estatal de Investigación