Structural analysis of caspase-1 inhibitors derived from Tethering

O’Brien, Tom; Fahr, B.T.; Sopko, Michelle M.; Lam, Joni; Waal, Nathan D.; Raimundo, Brian C.; Purkey, Hans E.; Pham, Phuongly; Romanowski, M.J.

doi:10.1107/s1744309105010109

Cited by 29 publications

(24 citation statements)

References 37 publications

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“…This approach was used to generate a small molecule inhibitor (SP4206, K d ~70 nM) of the IL-2 interaction with IL-2 receptor [41][42][43], inhibitors (K i ~7-140 nM) of caspase-1 [44] and binders [12-45 nM] of bovine carbonic anhydrase (CA) [45]. The binding affinity (7-70 nM) of the HMSM constructs was much greater than their constituent small molecules (140 nM and higher) but much less than most HMPs (0.1-1 nM).…”

Section: Other Heterovalent Interactionsmentioning

confidence: 99%

Designer Peptides: Learning from Nature

Shrivastava¹,

Nunn²,

Tweedle³

2009

CPD

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Recent advances in designing peptide ligands for therapeutic targets are making peptides an attractive alternative to small molecules and proteins. It is now common to see peptides developed with affinities comparable to antibodies and specificities much better than small molecules or antibodies. This is especially true in the case of tumor targeting cytotoxic drugs or targeted diagnostics where peptides can be used as a delivery vehicle for drugs or diagnostics. Moreover, lessons learned from nature in understanding peptide ligands are proving to be useful in designing better antibodies and small molecule therapeutics.

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Section: Other Heterovalent Interactionsmentioning

confidence: 99%

Designer Peptides: Learning from Nature

Shrivastava¹,

Nunn²,

Tweedle³

2009

CPD

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“…The Tethering with Extenders approach was also used to identify inhibitors to the anti-inflammatory target caspase-1 [28]. In this case, one of the same Extenders previously designed for caspase-3 selected an entirely different set of fragments.…”

Section: Caspase-1mentioning

confidence: 99%

Tethering

Erlanson¹,

Ballinger²,

Wells³

2006

Methods and Principles in Medicinal Chemistry

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IntroductionOne of the common challenges throughout this book is how to identify small chemical fragments that bind weakly to target biological molecules. Among fragment-based approaches, Tethering is unique in using a covalent, reversible bond to stabilize the interaction between a fragment and a target protein [1,2].The general process is outlined in Fig. 14.1. First, a cysteine residue is either coopted or introduced in a target protein. Metaphorically, the cysteine residue serves as a fishing line to capture fragments (fish) that bind near the cysteine. The protein is incubated with pools of thiol-containing, small molecule fragments which are conjugated to a common, hydrophilic thiol (such as cysteamine) for improved water solubility. By controlling the redox conditions in the experiment with exogenous reducing agents, equilibria can be established so that the cysteine residue in the protein reversibly forms disulfide bonds with the individual fragments. In the absence of any affinity between a fragment and the protein, no fragment should bind more favorably than any other; a pool of fragments produces a statistical mixture of different protein-fragment complexes, as well as unmodified protein and cysteaminemodified protein. However, if a fragment has inherent affinity for the protein and binds near the cysteine residue, the fragment-protein conjugate is stabilized, and this complex predominates. A fragment thus selected can be easily identified by mass spectrometry of the equilibrium mixture, and if each fragment in a pool has a unique molecular weight, so do the resulting protein-fragment conjugates. While the identified fragments are often weak ligands, X-ray crystallography of the protein-fragment conjugates is often facilitated by the covalent bond. These captured fragments then serve as starting points for conversion to non-covalent ligands by chemical optimization and removal of the thiol functionality.In the following pages, we present an overview of the theory and uses of Tethering. After first considering the basis of the technique in thermodynamic terms (section 14.2), we show how the technology can be used in the active sites of enzymes to identify fragments (section 14.4), which can then be elaborated to more potent inhibitors. Section 14.5 considers how Tethering can be used to not only 285 Fragment-based Approaches in Drug Discovery. Edited

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“…13,14 Experimental techniques for fragment-based drug discovery have been discussed in previous reviews which contain a large number of applications. [15][16][17][18][19][20] Successful in vitro screening campaigns have been reported for several targets, and a non-exhaustive list includes b-secretase, 7,15,21,22 several protein kinases, [23][24][25][26][27] DNA gyrase, 28 caspase, 29,30 anthrax lethal factor, 31 and phosphodiesterase. 32 In this review, we focus on the computational methods for fragment-based docking developed in our research group.…”

Section: Introductionmentioning

confidence: 99%

Library screening by fragment‐based docking

Huang

Caflisch

2009

J of Molecular Recognition

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We review our computational tools for high-throughput screening by fragment-based docking of large collections of small molecules. Applications to six different enzymes, four proteases, and two protein kinases, are presented. Remarkably, several low-micromolar inhibitors were discovered in each of the high-throughput docking campaigns. Probable reasons for the lack of submicromolar inhibitors are the tiny fraction of chemical space covered by the libraries of available compounds, as well as the approximations in the methods employed for scoring, and the use of a rigid conformation of the target protein.

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Structural analysis of caspase-1 inhibitors derived from Tethering

Cited by 29 publications

References 37 publications

Designer Peptides: Learning from Nature

Designer Peptides: Learning from Nature

Tethering

Library screening by fragment‐based docking

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