Major sources of small molecule drugs are natural products (NP) and chemical synthesis (mostly organic synthesis). Historically, Humans have used NP, particularly plants, in the treatment of different diseases. Out of drugs approved between 1981 and 2019, two-thirds correspond to NP or related compounds, and the remaining one-third to synthetic methods. An overall challenge developing NP-based drugs is its structural complexity that is frequently associated with the difficulty to synthesize them. Continued efforts have been made to design compounds that resemble NP and are rich in sp atoms. An approach is to deconstruct NP into fragments and combine unrelated NP fragments into pseudo-NP using synthetic methods. Over the past few years, efforts have been made to compile a list of NPs. For instance, the second version of the COlleCtion of Open Natural prodUcTs (COCONUT) has 695,133 distinct structures. Similarity, Latin American countries have been assembling a unified and open-access Latin American Natural Products Database (LANaPDB) that gathers ten databases. The first version of LANaPDB had 12,959 chemical structures and the most recent version has 13,578 compounds. The integration of fragment-based drug design (FBDD) with other drug discovery approaches has become crucial in the development of new candidates. The increasing application of biophysical and biochemical techniques for fragment identification, alongside strategic library design, facilitates the transformation of fragments into promising chemical series. The significance of FBDD underscores its vital role in fostering innovative therapies and broadening the horizons of medicinal chemistry. FBDD utilizes small organic molecules with fewer than 20 non-hydrogen atoms, adhering to the "rule of three" (RO3), ensuring a more efficient exploration of chemical space. Sources such as natural products (NP) and synthetic libraries further enhance this process by providing fragments with ideal physicochemical properties for the creation of lead series.