Drug Design, Development and Therapy

Exploring Fragment-Based Approaches in Drug Discovery

With the emergence of fragment-based drug discovery (FBDD), the field of drug discovery has undergone significant changes. Unlike traditional high-throughput screening techniques, FBDD is based on identifying low molecular weight compounds (fragments) with a low affinity to the biological target. These initial fragment hits are then developed into drug-like molecules through a range of techniques, including fragment merging, growing, and linking, to produce a lead with a higher affinity.

FBDD has the capacity to streamline the drug discovery process by initiating a bottom-up process of combining fragments with high ligand efficiencies. Structural insights from X-ray crystallography have fostered that fragments with strong local interaction networks could be extended to target a wider binding site, often boosting the affinity substantially. The method not only increases the probability of identifying active compounds compared to random screening but also allows an in-depth exploration of the chemical and biological space surrounding these fragments. In 2024, 52 fragment-derived candidates had made it to different phases of clinical studies (phase 1–3), while seven drugs (Asciminib, Capivasertib, Erdafitinib, Pexidartinib, Sotorasib, Vemurafenib, and Venetoclax) have already been approved. This highlights the great relevance and potential of this approach for drug discovery.

To help raise the profile of this important area of research, Drug Design, Development and Therapy is publishing a timely Article Collection on fragment-based drug discovery. The Collection is led by Professor Anna K. H. Hirsch, Dr. Walid A. M. Elgaher, Prof. Oliver Koch, and the Editor in Chief, Professor Frank M. Boeckler.

Potential topics include, but are not limited to, the following:

1. Advancements in Fragment Screening Techniques
2. Specialized Fragment-Libraries and Library Design
3. Structural Biology and Fragment-Based Design
4. Chemical Biology and Fragment Evolution
5. Case Studies and Success Stories
6. Challenges and Future Directions

Please submit your manuscript on our website, using the promo code SODHO for 20% off the advertised article processing charge and to indicate that your manuscript will be considered for the “Advances in p53 Drug Discovery” Collection. Please review the journal’s aims and scope and author submission instructions prior to submitting a manuscript.

Please contact Haoyang Yi (Commissioning Editor) at [email protected] with any queries regarding this Article Collection.

Guest Advisors

Prof. Dr. Anna K. H. Hirsch, Saarland University, Germany

[email protected]

Anna Hirsch read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology, doing a research project with Prof. Timothy Jamison. She carried out her Master’s research project in the group of Prof. Steven V. Ley at the University of Cambridge. She received her Ph.D. from the ETH Zurich in 2008 and worked on the de novo structure-based design and synthesis of inhibitors for an anti-infective target enzyme in the group of Prof. François Diederich. Subsequently, she joined the group of Prof. Jean-Marie Lehn at the Institut de Science et d’Ingénierie Supramoléculaires (ISIS) in Strasbourg as an HFSP postdoctoral fellow, before taking up a position as assistant professor at the Stratingh Institute for Chemistry at the University of Groningen in 2010 where she was promoted to associate professor in 2015. In 2017, she moved to the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), where she heads the department for drug design and optimization. Her work focuses on anti-infective drug design by adopting rational approaches such as structure- and fragment-based drug design in combination with the target-guided strategies dynamic combinatorial chemistry and kinetic target-guided synthesis.

Dr. Walid A. M. Elgaher, Saarland University, Germany

[email protected]

Dr. Walid A. M. Elgaher studied Pharmacy at Assiut University (Egypt). He was awarded a scholarship from the German academic exchange service (DAAD) for doctorate study in Germany. In 2016, he got his Ph.D. in Medicinal Chemistry under the supervision of Prof. Rolf W. Hartmann, Saarland University. He then returned to Egypt and was appointed as a Lecturer of Pharmaceutical Organic Chemistry at the Faculty of Pharmacy, Assiut University. In 2017, he joined the group of Prof. Anna K. H. Hirsch as a postdoctoral fellow at HIPS, and since 2024 has been a habilitand at Saarland University. His work focuses on the application of modern drug design approaches tackling un(der)exploited therapeutic targets and the use of biophysical and computational techniques for drug discovery and optimization.

Prof. Dr. Oliver Koch, Universität Münster, Germany

[email protected]

Oliver Koch is Heisenberg-Professor of Computational Drug Discovery at the Institute of Pharmaceutical and Medicinal Chemistry, University of Münster. His interests lie in the development and application of computational methods in rational drug design with focus on ‘big data’ driven decisions and artificial intelligence combined with fragment- and structure-based design. The methods are applied to develop bioactive molecules and to understand selectivity, promiscuity and polypharmacology of protein-ligand interactions. In an interdisciplinary way, the in-silico work is combined with biochemical evaluation, x-ray crystallography and preparative organic synthesis. He received his Ph.D. in Pharmaceutical Chemistry in 2007 at Philipps-University Marburg in the group of Gerhard Klebe and also completed a postgraduate program computer science with focus on machine learning and data science. He worked as a postdoc at CCDC in Cambridge/UK and afterwards for MSD Animal Health Innovation GmbH, Schwabenheim, Germany. In 2012, he became an Independent Junior Group Leader of „In-silico Medicinal Chemistry“ at Technical University Dortmund, Germany. From 2019-22 he was Independent Group Leader for “Computational Medicinal Chemistry and Molecular Design” at University of Münster, where he became a Heisenberg-Professor for Computational Drug Discovery in 2022.

Prof. Dr. Frank M. Böckler, Eberhard Karls University Tübingen

[email protected]

At the Institute of Pharmaceutical Sciences, Frank Böckler heads the laboratory of Molecular Design & Pharmaceutical Biophysics, which combines Chemical Biology, Molecular and Structural Biology and Biophysics, as well as Computational Chemistry, Machine Learning and Molecular Design. In addition, he is a member of the Institute for Bioinformatics and Medical Informatics (IBMI). In 2004, he received his Ph.D. in Medicinal Chemistry with summa cum laude at Friedrich-Alexander University in Erlangen (Germany). Joining Prof. Sir Alan R. Fersht as a postdoc at the MRC Center for Protein Engineering in Cambridge/UK, he discovered p53 mutant stabilizers as potential new cancer therapeutics. In 2008, he was appointed Professor (W2tt) for Bioanalytics at Ludwig-Maximilians University (LMU) Munich, before moving to Tübingen in 2010 as a full professor. His work is dedicated to understanding molecular interactions, such as halogen and chalcogen bonds, as the foundation for chemical biology and drug discovery and to apply theoretical, fragment-based, biophysical, and structural methods to cancer research, particularly involving the human kinome and the network of the tumor suppressor p53.