Fragment-based lead discovery: challenges and opportunities

Sun, Chaohong; Petros, Andrew M.; Hajduk, Philip J.

doi:10.1007/s10822-011-9451-z

Cited by 25 publications

(13 citation statements)

References 26 publications

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“…Quite generally, the FBDD approach is most promising for drug design, given that a few fragments can sample vast amounts of chemical space, reducing the number of compounds for screening (Sun et al 2011). Fragments bound at various regions of IDPs can be linked together via an appropriate linker (Fig.…”

Section: Fragment-based Drug Discovery For Idpsmentioning

confidence: 99%

Druggability of Intrinsically Disordered Proteins

Joshi

Vendruscolo

2015

Advances in Experimental Medicine and Biology

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Although the proteins in all the current major classes considered to be druggable are folded in their native states, intrinsically disordered proteins (IDPs) are becoming attractive candidates for therapeutic intervention by small drug-like molecules. IDPs are challenging targets because they exist as ensembles of structures, thereby making them unsuitable for standard rational drug design approaches, which require the knowledge of the three-dimensional structure of the proteins to be drugged. As we review in this chapter, several different small molecule strategies are currently under investigation to target IDPs, including: (i) to stabilise IDPs in their natively disordered states, (ii) to inhibit interactions with ordered or disordered protein partners, and (iii) to induce allosteric inhibition. In this context, biophysical techniques, including in particular nuclear magnetic resonance (NMR) spectroscopy and small-angle X-ray scattering (SAXS) coupled with molecular dynamics simulations and chemoinformatics approaches, are increasingly used to characterize the structural ensembles of IDPs and the specific interactions that they make with their binding partners. By analysing the results of recent studies, we describe the main structural features that may render IDPs druggable, and describe techniques that can be used for drug discovery programs focused on IDPs.

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Section: Fragment-based Drug Discovery For Idpsmentioning

confidence: 99%

Druggability of Intrinsically Disordered Proteins

Joshi

Vendruscolo

2015

Advances in Experimental Medicine and Biology

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“…With the ability of NMR techniques, medicinal chemists were able to identify specific small molecules that were interacting with a protein receptor [115,116]. This can be a valuable tool in building new molecular blocks and constructing new leads.…”

Section: Fragment-based Designmentioning

confidence: 99%

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

Polański

Kurczyk²,

Bąk³

et al. 2012

CMC

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The concept of privileged structures/substructures (PS) is the idea that certain structural features produce biological effects more often than others. The PS method can be seen as an offspring of fragonomics, which is based on recent experimental measurements of protein-ligand interactions. If PS prove to be true, then chemical motives that enrich biological activity can be used when designing new drugs. However, PS remain controversial because we cannot be sure whether the excess of active structures does not result from an abundance in chemical libraries. In this review, we will focus, in particular, on the preferential organization of azanaphthalene scaffolds (AN) in drugs and natural products (NP), which are preferred by Nature in evolution. We will show that knowledge discovery in molecular databases can reveal interesting time-trends profiles for important classes of potentially privileged scaffolds. The chemical library of AN is dominated by monoaza-compounds, among which quinoline appears to be the most frequently investigated scaffold; however; more sophisticated database mining seems to indicate different PS patterns within the AN scaffold family.

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“…However, there are still several undesired drawbacks for this approach. The defects of the experimental fragment-based method include time consuming, costly, and low affinity of hits (21,29,30). Another complementary way to approach fragment-based drug discovery is the application of computational methods, which can offer several advantages: (1) computational methodologies can construct high-quality and diversified fragment libraries with both time and cost efficiencies(31,32); (2) computational approaches can easily explore larger fragment databases; (3) optimization strategies for improving the drug-likeness of the hits with computational tools have efficiency and flexibility (33).…”

Section: Introductionmentioning

confidence: 99%

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

Bian

Feng

Yang

et al. 2017

AAPS J

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GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases. The crystal structure of mGlu5 in the complex with the negative allosteric modulator mavoglurant was recently reported, providing a fundamental model for designing new allosteric modulators. Computational fragment-based drug discovery represents a powerful scaffold-hopping and lead structure-optimization tool for drug design. In the present work, a set of integrated computational methodologies was first used, such as fragment library generation and retrosynthetic combinatorial analysis procedure (RECAP) for novel compound generation. Then, the compounds generated were assessed by benchmark dataset verification, docking studies, and QSAR model simulation. Subsequently, structurally diverse compounds, with reported or unreported scaffolds, can be observed from top 20 in silico synthesized compounds, which were predicted to be potential mGlu5 modulators. In silico compounds with reported scaffolds may fill SAR holes in known, patented series of mGlu5 modulators. And the generation of compounds without reported tests on mGluR indicates that our approach is doable for exploring and designing novel compounds. Our case study of designing allosteric modulators on mGlu5 demonstrated that the established computational fragment-based approach is a useful methodology for facilitating new compound design in the future.

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Fragment-based lead discovery: challenges and opportunities

Cited by 25 publications

References 26 publications

Druggability of Intrinsically Disordered Proteins

Druggability of Intrinsically Disordered Proteins

Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

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