![]() As fragments can provide diverse compounds for optimization, the number of compounds in the fragment library is not a limitation factor. ![]() In a virtual screening, the fragment library can be expanded with increasing diversity as the screening can be accomplished in a short time. Researchers usually have their own customized libraries in FBDD and molecular weight of a fragment can be above 300 Da. Recent studies indicated that a fragment does not have to follow the rule-of-three as the fragment in screening utilizes simple organic compounds that can be modified efficiently ( Jhoti et al., 2013). It is suggested that fragments should follow the rules-of-three in which compounds have a molecular weight less than 300 Da, ClogP value less than three, and less than three hydrogen donors and acceptors ( Congreve et al., 2003). The term of fragment indicates that the molecular weight of compounds is relatively small, which gives rise to high ligand efficiency and provides more opportunities for growing the hits. There are no strict rules for the size and the number of compounds in a library. With more and more compounds developed through this method, FBDD will be playing essential roles in target-based drug discovery ( Whittaker et al., 2010 Jacquemard and Kellenberger, 2019). ![]() In this review, fragment library, methods utilized in fragment screening, strategies applied in fragment optimization and targets that have been studied using FBDD are summarized. To carry out a fragment screening experiment, following procedures are usually required, namely selecting a compound library, setting up a method for hits identification, determining structures of fragment-target complexes, developing an assay for analyzing structure-activity relationship (SAR) and designing a strategy to grow the fragment into a potent inhibitor ( Figure 1). With more and more compounds derived from FBDD entering different stages of clinical studies, this method has been highly recognized in drug discovery. Several drugs such as vemurafenib-an inhibitor of oncogenic B-RAF kinase activity derived from fragment-based approach have been approved by FDA ( Erlanson, 2012). With the development of new approaches in screening and progress made in structural biology, FBDD has been readily carried on and playing important roles in target-based drug discovery ( Bollag et al., 2010, 2012 Harner et al., 2013). ![]() These advantages have encouraged researchers to adopt this method to develop inhibitors of different types of targets. Although FBDD cannot replace high-throughput screening (HTS) campaigns in drug discovery, it has some attractive advantages such as saving experimental cost, offering diverse hits, and exhibiting multiple ways to develop novel compounds ( Erlanson et al., 2016). The identified hit is then grown into drug-like molecules through different strategies. ![]() These starting hits are usually identified from a compound library using sensitive biophysical methods. FBDD usually generates a compound starting from a chemical fragment with a low binding affinity to the target, low complexity in chemical structures and low molecular weight (less than 300 Da) ( Murray and Rees, 2009 Doak et al., 2016). As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.įragment-based drug design (FBDD) is an approach to develop potent compounds from fragments. This review elucidates fragment libraries, methods utilized in fragment identification/confirmation, strategies applied in growing the identified fragments into drug-like lead compounds, and applications of FBDD to different targets. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. Many potent compounds/inhibitors of diverse targets have been developed using this approach. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery.
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