Fragment-based approach to drug lead discovery: overview and advances in various techniques.

In the last 20 years the advent of new technologies, such as high-throughput screening (HTS) and combinatorial chemistry, has produced new tools for the discovery of biologically active molecules. In the past decade, fragment-based drug discovery has emerged as a more rational and focused approach that concentrates on the quality, rather than the quantity, of hits and leads. The principles behind this strategy are different from those that represented the basis of conventional HTS. The starting point of this approach is always a small chemical entity (typically MW 150-200), a fragment, with low affinity for the selected target. Fragments should satisfy key features such as diversity, reduced structural complexity, aqueous solubility and availability. Because of their small size, they occupy a smaller region of chemical space if compared with classical HTS compounds; hence, fragment libraries provide a good diversity with a relatively low number of compounds. Classical biochemical assays are often not suitable to detect the low binding affinities involved, so some well known biophysical techniques, such as nuclear magnetic resonance and x-ray, have been opportunely modified in order to render them able to perform the task. When selecting fragments suitable for subsequent optimization, a useful parameter has been introduced, the ligand efficiency, which is defined as the free energy of binding divided by the non-hydrogen atom count. Once selected, a fragment must undergo a heavy elaboration to improve binding affinity, at the same time acquiring drug-like properties. There are two main ways to go on at this point. The most common one is the so-called 'fragment evolution', consisting of a stepwise and systematic addition of chemical functionalities to the starting fragment core, together with a continuous feedback for pharmacological and physicochemical properties. The second one, less common but with great potential, is 'fragment linking': when two or more fragment hits are found to bind in adjacent regions of the target protein, they can be linked through appropriate spacers to rapidly produce a single molecule with much higher binding affinity. Two representative case histories are described: Abbott's ABT 518, an MMP (matrix metalloproteinase) inhibitor, and Eli-Lilly's LY-517717, an inhibitor of factor Xa serine protease. In addition, a list of molecules claimed to be derived from fragment approach and currently undergoing clinical trials is presented.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

In the last 20 years the advent of new technologies, such as high-throughput screening (HTS) and combinatorial chemistry, has produced new tools for the discovery of biologically active molecules.

Erfahren Sie, wie diese Forschung mit der klinischen Praxis verknüpft ist

More peer-reviewed studies in Klinische Studien.

• Leech Therapy for Knee Osteoarthritis — The Landmark RCT — Michalsen et al. (2003)
• Leech-Assisted Flap Salvage — Systematic Review of 277 Cases — Whitaker et al. (2012)
• Effects of hirudotherapy on liver functions, lipid profile, and insulin sensitivity in rats with metabolic syndrome — Bilden A et al. (2026)
• HIRUDOTHERAPY IN PRESBYACUZIS PRAECOX IN CLEAN-UP WORKERS AFTER THE CHORNOBYL ACCIDENT DURING THE POST-CATASTROPHE YEARS — Zabolotnyi D, Mishchanchuk N (2019)
• Wound healing potential of bark paste of Pongamia pinnata along with hirudotherapy: A case report — Balasooriya D, Karunarathna C, Uluwaduge I (2021)
• AIF-1 and RNASET2 Play Complementary Roles in the Innate Immune Response of Medicinal Leech — Baranzini N et al. (2019)
• Study on the effect of medicinal leech therapy (Hirudo medicinalis) on full-thickness excisional wound healing in the animal model — Zakian A et al. (2022)
• [Hirudo medicinalis-leech applications in plastic and reconstructive microsurgery--a literature review] — Knobloch K et al. (2007)
• The duration of rest and feeding greatly affects the re-breeding of ectoparasites: Hirudo verbana, Hirudo medicinalis and Hirudo orientalis — Aminov R, Frolov A, Aminova A (2022)
• Recombinant hirudin in clinical practice: focus on lepirudin — Greinacher A, Lubenow N (2001)

Browse all ASH-analysed research →