Fragment-Based Discovery of BACE1 Inhibitors Using Functional Assays

Godemann, Robert; Madden, J. Patrick; Krämer, Joachim; Smith, M. A.; Fritz, Ulrike; Hesterkamp, Thomas; Barker, John J.; Höppner, Sabine; Hallett, David J.; Cesura, Andrea M.; Ebneth, Andreas; Kemp, John A.

doi:10.1021/bi901061a

Cited by 52 publications

(29 citation statements)

References 33 publications

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“…SPR biosensor assays are often used in fragment-based drug discovery as an orthogonal, complementary technique to confirm and validate the direct measurement of the kinetics and affinity of fragment hits discovered by other screening methods (Huber, 2005;Geschwindner et al, 2007;Godemann et al, 2009;Cole et al, 2010). However, in recent years SPR biosensor screening has become a primary screening method for fragment-based drug discovery (Giannetti, 2011), as it has several practical advantages over other techniques.…”

Section: Spr Fragment Screeningmentioning

confidence: 99%

Fragment screening by SPR and advanced application to GPCRs

Shepherd

Hopkins

Navrátilová

2014

Progress in Biophysics and Molecular Biology

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Surface plasmon resonance (SPR) is one of the primary biophysical methods for the screening of low molecular weight 'fragment' libraries, due to its low protein consumption and 'label-free' methodology. SPR biosensor interaction analysis is employed to both screen and confirm the binding of compounds in fragment screening experiments, as it provides accurate information on the affinity and kinetics of molecular interactions. The most advanced application of the use of SPR for fragment screening is against membrane protein drug targets, such G-protein coupled receptors (GPCRs). Biophysical GPCR assays using SPR have been validated with pharmacological measurements approximate to cell-based methods, yet provide the advantage of biophysical methods in their ability to measure the weak affinities of low molecular weight fragments. A number of SPR fragment screens against GPCRs have now been disclosed in the literature. SPR fragment screening is proving versatile to screen both thermostabilised GPCRs and solubilised wild type receptors. In this chapter, we discuss the state-of-the-art in GPCR fragment screening by SPR and the technical considerations in performing such experiments.

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Section: Spr Fragment Screeningmentioning

confidence: 99%

Fragment screening by SPR and advanced application to GPCRs

Shepherd

Hopkins

Navrátilová

2014

Progress in Biophysics and Molecular Biology

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“…Plexxikon's effort ultimately led to the identification of PLX4032 (Vemurafenib) (see section 4). Other groups also used high concentration biochemical screening as their primary fragment screening approach to identify inhibitors of phosphatidylinositol-3 kinase [88], phosphoinositide-dependent kinase-1 (PDK1) [89] and betasecretase (BACE-1) [90]. Nowadays, with significant successes of using high concentration screening by biological assays reported, many groups in pharmaceutical industry are using fragments in HTS screening at higher concentration to develop target focused sets of fragments for further biophysical screening [15].…”

Section: Biochemical Assays/high Concentration Screeningsmentioning

confidence: 99%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

151

102

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Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X-ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches.

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“…Co-crystallization of a 1 mM inhibitor with recombinant BACE-1 provided the basis for drug optimization. Two iterations of synthesis achieved a 100-fold increase in potency while keeping the MW to <400 and provided the proof that small fragment hits could provide BACE-1 inhibitors active in vitro [108] (21) as illustrated in Fig. (4).…”

Section: New Scaffoldsmentioning

confidence: 91%

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

Evin¹,

Lessène²,

Wilkins

2011

RPCN

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Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as BACE-1) or γ-secretase, or by interfering with Aβ aggregation, or by promoting Aβ clearance. Targeting BACE-1, the proteolytic enzyme that initiates Aβ formation, has generated a lot of research interest recently and is currently thought to be one of the most promising therapeutic approaches. In this review, we summarize and discuss the latest patents and publications describing BACE-1 inhibitors, principally focussing on their drug properties and performance in preclinical trials.

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Fragment-Based Discovery of BACE1 Inhibitors Using Functional Assays

Cited by 52 publications

References 33 publications

Fragment screening by SPR and advanced application to GPCRs

Fragment screening by SPR and advanced application to GPCRs

Fragment Based Drug Design: From Experimental to Computational Approaches

BACE Inhibitors as Potential Drugs for the Treatment of Alzheimers Disease: Focus on Bioactivity

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