Application of Fragment-Based Drug Discovery to Versatile Targets.

Qingxin Li

doi:10.3389/fmolb.2020.00180

Abstract

Fragment-based drug discovery (FBDD) is a powerful method to develop potent small-molecule compounds starting from fragments binding weakly to targets. As FBDD exhibits several advantages over high-throughput screening campaigns, it becomes an attractive strategy in target-based drug discovery. Many potent compounds/inhibitors of diverse targets have been developed using this approach. Methods used in fragment screening and understanding fragment-binding modes are critical in FBDD. 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. As FBDD can be readily carried out through different biophysical and computer-based methods, it will play more important roles in drug discovery.

Highlights

Fragment-based drug design (FBDD) is an approach to develop potent compounds from fragments
This study provides an evidence that surface plasmon resonance (SPR) can be performed in complicated systems in which multiple proteins are present
The availability of 19F-labeled compound libraries makes 19F-nuclear magnetic resonance (NMR) more powerful in Fragment-based drug discovery (FBDD) (Kang, 2019b; Lingel et al, 2020). 19F-NMR is most attractive in fragment screening for the reason that a mixture of compounds can be screened and the correct hit can be readily picked out, making it become a high-throughput method

Summary

INTRODUCTION

Fragment-based drug design (FBDD) is an approach to develop potent compounds from fragments. 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) These starting hits are usually identified from a compound library using sensitive biophysical methods. 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). Fragments with low binding affinities might not give measurable results making this method unable to identify weak binders It is a time-consuming technique and a large amount of protein sample is required in comparison with other techniques such as DSF. SPR-based fragment screening has been successfully applied to different targets such as carbonic anhydrase II (Navratilova and Hopkins, 2010), thrombin, carbonic anhydrase, glutathione-Stransferase (Hämäläinen et al, 2008)

19 F-NMR 31 P-NMR 1D-NMR NOESY PRE

Other Methods

Methods

Findings

CONCLUSION