ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs


Proteolysis-targeting chimeras (PROTACs) have emerged as a promising class of therapeutics for the treatment of various human diseases. These innovative molecules harness the tremendous potential of E3 ligases, a group of proteins responsible for marking target proteins for degradation through the ubiquitin-proteasome system. By leveraging this natural cellular pathway, PROTACs offer a unique approach to selectively eliminate disease-causing proteins and hold significant advantages over traditional small-molecule inhibitors. For instance, PROTACs can hold significant potential in oncology by selectively targeting oncogenic proteins, such as transcription factors or kinases, which play pivotal roles in cancer progression. By degrading these proteins, PROTACs impede their aberrant signaling, potentially leading to tumor regression. The success of PROTAC molecules is demonstrated by currently some molecules are being tested in clinical trials such as ARV-110 which targets the androgen receptor for the potential treatment of prostate cancer and ARV-471, another PROTAC designed to degrade the estrogen receptor for the potential treatment of breast cancer.

PROTACs consist of three essential components: a ligand that binds to the target protein, a ligand that binds to an E3 ubiquitin ligase enzyme, and a linker connecting the two ligands. The ligand for the target protein enables its recognition and binding, while the ligand for the E3 ubiquitin ligase facilitates the recruitment of the cellular protein degradation machinery. Despite the presence of several databases focusing on E3 ligases, the choice of functional ligases for PROTAC development remains limited, encompassing only 1.6% of the available pool. This limitation arises due to the incomplete understanding of the structures and known ligands of E3 ligases. Current databases fail to provide detailed studies covering the 3D structure of E3 ligases and their pockets, hampering the identification of suitable ligases for PROTAC design.

To address these limitations, a new platform called ELIOT (E3 LIgase pocketOme navigaTor) has been introduced by Laboratory of Chemoinformatic from University of Perugia in Italy together with  Molecular Discovery Ltd team in England . ELIOT serves as an accurate and comprehensive platform containing the E3 ligase pocketome, facilitating the navigation and selection of new E3 ligases and ligands for PROTAC design. The research work is now published in the peer-reviewed journal, Chemical Biology & Drug Design.

According to the authors, a key feature of ELIOT is the characterization of all E3 ligase pockets using innovative 3D descriptors, including a novel scoring system called the PROTAC-ability score. These descriptors enable a detailed assessment of the suitability of E3 ligase pockets for PROTAC design, guiding researchers in identifying ligases with optimal binding characteristics.

ELIOT also offers similarity analyses between E3 pockets, providing insights into structural similarities and differences among various ligases. This comparative analysis allows researchers to explore the relationships between different pockets, facilitating the selection of ligands and enhancing the efficiency of PROTAC design.

Recognizing the importance of tissue specificity and the degree of involvement of E3 ligases in specific cancer types, ELIOT includes annotations for each ligase. These annotations help researchers select appropriate E3 ligases for PROTAC design, taking into account their relevance to specific diseases and their potential for improved specificity.

The introduction of ELIOT has brought about a transformative shift in PROTAC development. By providing a comprehensive and accurate database of E3 ligase pockets, this platform empowers researchers to explore untapped potential and expand the repertoire of available ligases for PROTAC design. The detailed 3D structural information and scoring system facilitate informed decision-making, enhancing the chances of successful PROTAC development.

With ELIOT’s guidance, researchers can navigate through the E3 ligase pocketome and identify ligases that offer superior binding properties for the design of highly specific and effective PROTACs. This advancement holds great promise for the development of targeted therapies, allowing for precise degradation of disease-causing proteins while sparing healthy ones.

In conclusion, the introduction of ELIOT as a comprehensive platform for E3 ligase pocketome exploration and selection can revolutionize the field of PROTAC development. By providing detailed structural information, scoring systems, and tissue-specific annotations, ELIOT will empower researchers to design PROTACs with improved specificity and efficacy. This platform unlocks the vast potential of E3 ligases, paving the way for the development of novel therapeutics for a wide range of human diseases.

ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs - Medicine Innovates

About the author

Gabriele Cruciani is full professor of Organic Chemistry since 2005 at the Chemistry Department of the University of Perugia (Italy) and scientific director in several companies. He is also the scientific director of the Human Cytochrome Consortium Initiative, a Consortium of eight pharmaceutical companies which cooperate in studying the problems on human metabolism of drugs. His scientific activity is documented by over 130 papers, all published on international journals, and by the book “Molecular Interaction Fields” (Wyley-VCH Editor). Thanks to the outstanding results of his research activity, he has received the “Hansch Award” during the Gordon Conference of the QSAR and Modeling Society in Tilton (USA) in 2001 for his researches on QSAR and computer chemistry, the Research award from the Organic Division of the Italian Chemical Society in 2005, and the “Novartis Lectureship Award” in 2009 at Basel and Boston.

About the author

Lydia Siragusa is a senior researcher at Molecular Horizon srl and Molecular Discovery Ltd. She obtained her PhD degree in Organic Chemistry on 2013 at University of Perugia (Italy), under the supervision of Prof. Gabriele Cruciani. During the PhD her study was focused on the development of the GRID MIFs-based (Molecular Interaction Fields) methods applied to protein-protein comparison. During her PhD, she spent 10 months at the Institute for Research for Biomedicine (IRB, Barcelona, Spain), under the supervision of Patrick Aloy in the Structural Bioinformatic and Network Biology laboratory. Her job focuses on the development and the applications of methodologies for characterizing and comparing protein binding sites based on the GRID MIFs. Such methods are applied for rationalizing drug side-effects, ligand selectivity, catalysis specificity, de novo drug discovery, chemical food safety and polypharmacology through a 3D structural point of view.

About the author

Tommaso Palomba is a researcher at Molecular Discovery Ltd. He obtained his PhD degree in Theoretical Chemistry and Computational Modelling on 2023 at University of Perugia (Italy), under the supervision of Prof. Gabriele Cruciani. During the PhD he addressed several hot topics in the field of drug design and discovery, especially exploiting the rational use of computational techniques based on GRID MIFs-based (Molecular Interaction Fields) for the characterization of proteins and their interactions with small molecules. His job focuses on the development of an E3 ligase pocketome in order to innovatively characterize the E3 ligase subfamily to aid the promising growth of the PROTAC technology. Moreover, he spent 6 months within the computational chemistry team of Sosei Heptares Ltd (Cambridge, UK), under the supervision of the Head of the team Chris de Graaf, by studying different GPCR systems and the key role of the water molecules in binding exploiting the GRID algorithm for water molecules prediction. He also worked on side projects concerning applications of drug-repurposing, pockets comparison, off-target evaluation and metabolism prediction.


Palomba T, Baroni M, Cross S, Cruciani G, Siragusa L. ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs. Chem Biol Drug Des. 2023 Jan;101(1):69-86. doi: 10.1111/cbdd.14123.