Exploring protein–ligand recognition with Binding MOAD

Smith, Richard; Hu, Liegi; Falkner, Jayson A.; Benson, Mark L.; Nerothin, Jason; Carlson, Heather A.

doi:10.1016/j.jmgm.2005.08.002

Cited by 56 publications

(57 citation statements)

References 55 publications

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“…The challenges associated with targeting Aβ aggregation are substantial, with the most obvious obstacle being the sheer size and geometry of the protein interaction surface. First, the regions of protein-protein interactions are approximately 1500-3000 Å 2 [37][38][39][40] , whereas protein-small molecule interaction regions are only about 300-1000 Å 2 [41,42] . Thus, small molecules are often unable to produce sufficient steric hindrance to inhibit Aβ aggregation [43] .…”

Section: Problems Associated With Inhibiting Aβ Aggregationmentioning

confidence: 99%

Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

2011

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Amyloid β (Aβ) peptides have long been viewed as a potential target for Alzheimer's disease (AD). Aggregation of Aβ peptides in the brain tissue is believed to be an exclusively pathological process. Therefore, blocking the initial stages of Aβ peptide aggregation with small molecules could hold considerable promise as the starting point for the development of new therapies for AD. Recent rapid progresses in our understanding of toxic amyloid assembly provide a fresh impetus for this interesting approach. Here, we discuss the problems, challenges and new concepts in targeting Aβ peptides.

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Section: Problems Associated With Inhibiting Aβ Aggregationmentioning

confidence: 99%

Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

2011

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“…Our two-sample T-tests indicate that such mean value is statistically larger than that of category III; whereas it is not statistically different from that of category I at the 95% confidence level (Table 4). Metal-containing complexes have not been addressed adequately in previous surveys on protein-ligand complexes [7,8,10] . Our results suggest that the complexes in the second category, which all have a zinc cation involved in protein-ligand binding, can be safely regarded as covalently bound protein-ligand complexes as those in the first category.…”

Section: Comparison Of the Binding Constants Of Covalent And Noncovalmentioning

confidence: 99%

“…We also analyzed the correlation between binding constants and sizes of ligands for both covalent and noncovalent complexes (Figure 8). Here, the total number of the nonhydrogen atoms on a given ligand is used as an indicator of its size, a method adopted by both Kuntz et al [7] and Carlson et al [8] in their surveys. This property actually correlated very well with DSASA across the entire data set, which is consistent with Carlson's observation.…”

Section: On Houk's Hypothesis Of Enzyme Proficiencymentioning

confidence: 99%

“…They suggested that "van der Waals interactions and hydrophobic effects provide a reasonable basis for understanding binding affinities across the entire set of ligands". Recently, Carlson et al conducted another survey [8] on the binding affinities of nearly 1800 protein-ligand complexes collected in their Binding MOAD database, [9] which can be considered as an extension to Kuntz's study. Their results confirmed the correlation between binding affinity and ligand size as proposed by Kuntz et al Houk et al conducted a survey on the binding affinities of a broader range of binding systems, including synthetic host-guest complexes, various protein-ligand complexes, and enzyme-transition state complexes.…”

Section: Introductionmentioning

confidence: 99%

“…be drawn since the total number of such samples in their survey was really small (< 10). Carlson et al [8] did not address covalently bound protein-ligand complexes in their survey since the Binding MOAD database does not contain such samples. In contrast, Houk et al [17,18] paid special attention to the role of covalent bond formation in binding.…”

Section: Introductionmentioning

confidence: 99%

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A Statistical Survey on the Binding Constants of Covalently Bound Protein–Ligand Complexes

Liu

et al. 2010

Molecular Informatics

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We have conducted a statistical survey to compare the binding constants of covalently and noncovalently bound protein-ligand complexes as two groups. In our study, a total of 1602 complexes formed between various types of proteins and small-molecule ligands were selected from the PDBbind database (version 2008), all of which had high-resolution three-dimensional structures and reliable experimentally measured binding constants. These complexes were further classified as 79 covalent complexes, 131 Zn-containing complexes, and 1392 noncovalent complexes. Covalent complexes formed through reversible mechanisms are found to be associated with higher binding constants than noncovalent complexes. Two-sample T-test indicates that the difference is statistically significant. The advantage, however, is only modest (<20 folds). The same trend is also observed on a set of covalent and noncovalent complexes formed by thrombin. Our results indicate that reversible covalent bonding formed between protein and ligand will not automatically lead to a much tighter binding in general. Thus, our survey does not provide any supporting evidence for Houk's hypothesis which states that covalent bonding formed between enzyme and transition state accounts for the extraordinary proficiency of enzymes.

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Biophysics of Protein–Protein Interactions

Luque¹

2010

Protein Surface Recognition

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Exploring protein–ligand recognition with Binding MOAD

Cited by 56 publications

References 55 publications

Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

A Statistical Survey on the Binding Constants of Covalently Bound Protein–Ligand Complexes

Biophysics of Protein–Protein Interactions

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