Mohammad Javed* 1
Sita Kumari 2
The identification and creation of new therapeutic compounds constitute one of the major difficulties in pharmaceutical chemistry. Conventional methods for drug discovery, especially high-throughput screening (HTS), encompass evaluating extensive collections of drug-like compounds against target proteins. Though HTS has greatly aided in discovering new chemical entities, this traditional approach is becoming increasingly constrained by rising development expenses, prolonged periods, and the challenges in targeting structurally complex proteins. In the last twenty years, fragment-based drug discovery (FBDD) has become a transformative approach in pharmaceutical chemistry, providing a complementary and frequently better option to conventional screening techniques. [1, 2] FBDD embodies a bottom-up strategy for drug development that starts with small, low-molecular-weight entities known as "fragments." In contrast to traditional HTS that usually examines extensive libraries of drug-like substances with molecular weights over 400 Da, FBDD employs molecular fragments that typically fall between 150 and 300 Da, following the "rule of three" guidelines. This essential difference in strategy offers multiple strategic benefits: fragments show enhanced binding efficiency (ligand efficiency), necessitate fewer compounds for screening because of improved exploration of chemical space, and allow for the discovery of novel pharmacophores that traditional HTS might miss. The theoretical basis of FBDD is founded on the idea that small molecular fragments, despite having weak individual binding affinities with protein targets, can effectively act as initial points for methodical development into strong lead compounds via rational medicinal chemistry. Starting with fragments that engage particular binding sites on target proteins allows medicinal chemists to steer further optimization by utilizing comprehensive structural data acquired from diverse biophysical techniques, which ensures that the transition from fragment to lead compound is intentional and systematic instead of accidental. The influence of FBDD on pharmaceutical chemistry and the development of clinical drugs has been significant and increasing. As of now, eight drugs identified through FBDD have gained FDA approval, and over 50 compounds derived from FBDD have moved into clinical development spanning various therapeutic fields such as oncology, infectious diseases, and neurology. Prominent instances comprise vemurafenib (BRAF blocker for melanoma), venetoclax (BCL-2 blocker for blood cancers), pexidartinib (CSF-1R blocker), erdafitinib (pan-FGFR blocker), and asciminib (ABL allosteric blocker for chronic myeloid leukemia). This review offers an in-depth analysis of fragment-based drug discovery, covering its historical evolution, theoretical foundations, screening and optimization techniques, applications in difficult target categories, and the incorporation of new computational and AI-driven methods.
10.5281/zenodo.18898200