Fragment-Based Drug Development

The theoretical basis of FDBB is that drug molecules function through their fragments. The FDBB strategy is to screen out active fragments, extend them through combinations of different fragments, and optimize them in order to obtain new drug molecules. The main advantages of the FBDD strategy are low experimental cost, high selectivity, small molecular weight, fewer invalid groups, and easier structural optimization in the later stage. So far, FBDD has become the mainstream method for drug development targeting protein targets. Vemurafenib (PLX18; HY-12057) is a treatment drug for unresectable or metastatic melanoma with positive BRAF V600 mutation and also the first drug developed based on the FBBD strategy. It was approved by FDA in 2011. At present, more than 40 drugs have entered the clinical research stage around FBDD technology, and four drugs have been successfully launched.

1.Establishing a high-quality fragment library
All fragments in the FBDD database are filled with the RO3 principle, which means molecular weight ≤300, hydrogen bond donor and acceptor ≤3, number of rotatable bonds ≤3, and cLogP<3.
2. Screening and identification of active fragments weakly bound to target proteins
After the establishment of the fragment library, the most crucial step is to screen and identify active fragments that are weakly bound to the target protein. The main technologies currently used to identify fragment compounds are as follows:

Identification Techniques for Major Fragment Compounds

3. Modification and extension of active fragments
After screening out the active fragment compounds, the fragment compounds need to be structurally modified to obtain highly active Lead compound. At present, the most important fragment extension methods include fragment-linking, fragment-merging and fragment-growing.

Modification and Extension of Active Fragments

MedChemExpress (MCE) has collected and sorted out a large number of fragment compounds. All fragment compounds strictly comply with the RO3 principle, and they are characterized by structural diversity and stability, low complexity, high solubility, and high purity. It also provides some characteristic fragment compound libraries, such as F-Fragments Library, Cysteine Targeted Covalent Fragment Library, and 3D Diverse Fragment Library, providing an important source for the screening and development of Lead compound.