Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

Smith, Adam J. T.; Zhang, Xiyun; Leach, Andrew G.; Houk, K. N.

doi:10.1021/jm800498e

Cited by 161 publications

(164 citation statements)

References 112 publications

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“…Second, states with low statistical weights usually cannot be characterized, either structurally or biochemically. 140 In addition, it is difficult to achieve a high throughput along with accurate thermodynamic information. [141][142][143][144][145] Simulations are an alternative, and simple models such as the LIE and Molecular Mechanics Poisson-Boltzmann approaches (''MM-PBSA'') have become widespread.…”

Section: Discussionmentioning

confidence: 99%

Alchemical free energy simulations for biological complexes: powerful but temperamental …

Aleksandrov

Thompson

Simonson

2009

J of Molecular Recognition

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Free energy simulations compare multiple ligand:receptor complexes by "alchemically" transforming one into another, yielding binding free energy differences. Since their introduction in the 1980s, many technical and theoretical obstacles were surmounted, and the method ("MDFE," since molecular dynamics are often used) has matured into a powerful tool. We describe its current status, its effectiveness, and the challenges it faces. MDFE has provided chemical accuracy for many systems but remains expensive, with significant human overhead costs. The bottlenecks have shifted, partly due to increased computer power. To study diverse sets of ligands, force field availability and accuracy can be a major difficulty. Another difficulty is the frequent need to consider multiple states, related to sidechain protonation or buried waters, for example. Sophisticated, automated methods to sample these states are maturing, such as constant pH simulations. Meanwhile, combinations of MDFE and simpler approaches, like continuum dielectric models, can be very effective. As illustrations, we show how, with careful force field parameterization, MDFE accurately predicts binding specificities between complex tetracycline ligands and their targets. We describe substrate binding to the aspartyl-tRNA synthetase enzyme, where many distinct electrostatic states play a role, and a histidine and a Mg(2+) ion act as coupled switches that help enforce a strict preference for the aspartate substrate, relative to several analogs. Overall, MDFE has achieved a predictive status, where novel ligands can be studied and molecular recognition elucidated in depth. It should play an increasing role in the analysis of complex cellular processes and biomolecular engineering.

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Section: Discussionmentioning

confidence: 99%

Alchemical free energy simulations for biological complexes: powerful but temperamental …

Aleksandrov

Thompson

Simonson

2009

J of Molecular Recognition

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“…The error analysis results are given in Table S5 and Figure 5. The error analysis on the experimental data (Fig 5A) showed that the experimental data for the 5 series is more reliable than the 3 series, which shows a noticeable spread in R 2 and PI values. This indicates that uncertainties in the experimental data in the 3 series limit the maximal correlations that may be realistically achieved.…”

Section: Soft-core Potentials Occasionally Introduce Serious Artefactsmentioning

confidence: 95%

“…[1][2][3] To this end, the free energy of binding is frequently used to quantify the strength of protein-ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

Calabró

Woods²,

Powlesland

et al. 2016

J. Phys. Chem. B

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“…[29,30] Another notable fact is that no covalent complex in our data set exhibits an extremely tight binding, i.e. logK a > 11, a criterion adopted by both Kuntz et al [7] and Houk et al [10,17,18] in their studies. On the other hand, no covalent complex in our data set exhibits an extremely loose binding either, i.e.…”

Section: Comparison Of the Binding Constants Of Covalent And Noncovalmentioning

confidence: 99%

“…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. They even proposed that the extraordinary binding between enzyme and transition state should be attributed to covalent bond formation.…”

Section: Introductionmentioning

confidence: 99%

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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Beyond Picomolar Affinities: Quantitative Aspects of Noncovalent and Covalent Binding of Drugs to Proteins

Cited by 161 publications

References 112 publications

Alchemical free energy simulations for biological complexes: powerful but temperamental …

Alchemical free energy simulations for biological complexes: powerful but temperamental …

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

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

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