Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

Röhrig, Christoph H.; Loch, Caroline; Guan, Jia-Ying; Siegal, Gregg; Overhand, Mark

doi:10.1002/cmdc.200600296

Cited by 20 publications

(22 citation statements)

References 45 publications

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“…using K D A , K D B and a factor termed linking coefficient, E (M −1 ) 5. Linking coefficient (also referred to as the theoretical fragment linker factor ( f L ))21 is a convenient measure to quantify the efficiency of a fragment linking and is related to Jencks’ connection Gibbs free energy by equation (3) at a given temperature …”

Section: Fragment Linking Backgroundmentioning

confidence: 99%

Compound Design by Fragment‐Linking

Ichihara

Barker

Law

et al. 2011

Molecular Informatics

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The linking together of two fragment compounds that bind to distinct protein sub-sites can lead to a superadditivity of binding affinities, in which the binding free energy of the linked fragments exceeds the simple sum of the binding energies of individual fragments (linking coefficient E<1). However, a review of the literature shows that such events are relatively rare and, in the majority of the cases, linking coefficients are far from optimal being much greater than 1. It is critical to design a linker that does not disturb the original binding poses of each fragment in order to achieve successful linking. However, such an ideal linker is often difficult to design and even more difficult to actually synthesize. We suggest that the chance of achieving successful fragment linking can be significantly improved by choosing a fragment pair that consists of one fragment that binds by strong H-bonds (or non-classical equivalents) and a second fragment that is more tolerant of changes in binding mode (hydrophobic or vdW binders). We also propose that the fragment molecular orbital (FMO) calculations can be used to analyse the nature of the binding interactions of the fragment hits for the selection of fragments for evolution, merging and linking in order to optimize the chance of success.

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Section: Fragment Linking Backgroundmentioning

confidence: 99%

Compound Design by Fragment‐Linking

Ichihara

Barker

Law

et al. 2011

Molecular Informatics

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“…First, they impose distance, angle, and stereochemical constraints on the linked fragments, giving rise to a highly specific interaction. Second, linkers are far from passive connectors and can contribute directly to the efficacy of the molecule (Schuffenhauer et al 2005;Rohrig et al 2007;Chung et al 2009). …”

Section: Cooperativity Through Fragment Linkingmentioning

confidence: 99%

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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“…The binding process of the ligands was preliminary studied by means of photophysical measurements in solution investigating the fluorescence quenching of the tryptophan residue in the binding pocket of FKBP12 [6]. An efficient fluorescence quenching of FKBP12 was observed upon addition of the ligands in solution.…”

Section: Resultsmentioning

confidence: 99%

Nanolayers for early diagnostics of proteins involved in degenerative amyloidosis

Martina

Mercatelli

Baglioni

et al. 2013

MATEC Web of Conferences

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Abstract. FK-506 binding protein (FKBP12) is a protein of the family of immunophilins, involved in many neurodegenerative diseases such as Alzheimer's syndrome where FKBP12 is known to be over-expressed in early stages of the disease. We designed and built Langmuir-Blodgett nanostructures incorporating ligands with high affinity for FKBP12: Tacrolimus (FK506) and Rifaximin as candidate nanosensors to detect low FKBP12 concentration in the initial phase of the amyloidosis. The binding process of the different ligands has been studied by means of photophysical measurements investigating the fluorescence quenching of the tryptophan residue in the binding pocket of FKBP12 by addition of the ligand in solution. Immobilization of the ligands was achieved adopting biomimetic strategy: phospholipid Langmuir-Blodgett films are proposed as nanoscaffolds for ligand inclusion. Several phospholipid nanoarchitectures differing in lipid composition, fluidity, number of layers and method of production (incubation versus co-spreading) were screened. The results have shown that both FK506 and Rifaximin ligands penetrate the lipid matrix either as monomers or as aggregates depending on their initial concentration. More importantly, the experiments demonstrated that the ligands in the LB scaffolds efficiently quench FKBP12 fluorescence in solution as a consequence of ligand binding to the protein.

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Fragment‐Based Synthesis and SAR of Modified FKBP Ligands: Influence of Different Linking on Binding Affinity

Cited by 20 publications

References 45 publications

Compound Design by Fragment‐Linking

Compound Design by Fragment‐Linking

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Nanolayers for early diagnostics of proteins involved in degenerative amyloidosis

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