Computational modeling approaches to quantitative structure–binding kinetics relationships in drug discovery

Benedetti, Pier G. De; Fanelli, Francesca

doi:10.1016/j.drudis.2018.03.010

Cited by 19 publications

(16 citation statements)

References 77 publications

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“…Additionally, fluorinating pharmaceuticals has several positive effects, including enhanced binding and metabolic stability (4), and there are numerous fluorine compound and fragment libraries for drug discovery (5)(6)(7). It has also been suggested that the kinetics of drug-protein interactions are as important as K D or half maximal inhibitory con-centration (IC 50 ) values when considering hit-to-lead optimization and designing an effective, bioavailable therapeutic (8)(9)(10)(11)(12). Here, we show how combining fluorine labeling of a protein (13), 19 F NMR, and lineshape analysis can provide quantitative, low-cost access to the kinetics and equilibrium thermodynamics of protein-peptide interactions.…”

Section: Introductionmentioning

confidence: 99%

Rapid Quantification of Protein-Ligand Binding via 19F NMR Lineshape Analysis

Stadmiller

Aguilar

Waudby

et al. 2020

Biophysical Journal

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Fluorine incorporation is ideally suited to many NMR techniques, and incorporation of fluorine into proteins and fragment libraries for drug discovery has become increasingly common. Here, we use one-dimensional 19 F NMR lineshape analysis to quantify the kinetics and equilibrium thermodynamics for the binding of a fluorine-labeled Src homology 3 (SH3) protein domain to four proline-rich peptides. SH3 domains are one of the largest and most well-characterized families of protein recognition domains and have a multitude of functions in eukaryotic cell signaling. First, we showe that fluorine incorporation into SH3 causes only minor structural changes to both the free and bound states using amide proton temperature coefficients. We then compare the results from lineshape analysis of one-dimensional 19 F spectra to those from two-dimensional 1 H-15 N heteronuclear single quantum coherence spectra. Their agreement demonstrates that one-dimensional 19 F lineshape analysis is a robust, low-cost, and fast alternative to traditional heteronuclear single quantum coherence-based experiments. The data show that binding is diffusion limited and indicate that the transition state is highly similar to the free state. We also measured binding as a function of temperature. At equilibrium, binding is enthalpically driven and arises from a highly positive activation enthalpy for association with small entropic contributions. Our results agree with those from studies using different techniques, providing additional evidence for the utility of 19 F NMR lineshape analysis, and we anticipate that this analysis will be an effective tool for rapidly characterizing the energetics of protein interactions.

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Section: Introductionmentioning

confidence: 99%

Rapid Quantification of Protein-Ligand Binding via 19F NMR Lineshape Analysis

Stadmiller

Aguilar

Waudby

et al. 2020

Biophysical Journal

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“…Although thermodynamic properties (e.g., IC 50 , EC 50 and equilibrium dissociation constant (k d )) have been regarded as key indicators of drug potency, mounting evidence suggests that thermodynamic properties may not be the only measures of drug potency. Recently, it has become increasingly apparent that kinetic properties-especially dissociation rate constant (k off ) or drug-target residence time (τ)-are more important for drug potency and are gradually being used in real-world lead optimization and drug design [1][2][3][4][5]. At present, kinetic properties are mainly determined by laboratory techniques, such as capillary electrophoresis, [6] affinity chromatography [7] and surface plasmon resonance methods [8,9], etc.…”

Section: Introductionmentioning

confidence: 99%

In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method

Huang

Chen

Mei

et al. 2020

IJMS

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Accumulated evidence suggests that binding kinetic properties—especially dissociation rate constant or drug-target residence time—are crucial factors affecting drug potency. However, quantitative prediction of kinetic properties has always been a challenging task in drug discovery. In this study, the VolSurf method was successfully applied to quantitatively predict the koff values of the small ligands of heat shock protein 90α (HSP90α), adenosine receptor (AR) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that few VolSurf descriptors can efficiently capture the key ligand surface properties related to dissociation rate; the resulting models demonstrated to be extremely simple, robust and predictive in comparison with available prediction methods. Therefore, it can be concluded that the VolSurf-based prediction method can be widely applied in the ligand-receptor binding kinetics and de novo drug design researches.

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“…Molecular docking by a computer is also an important method for evaluating drug target binding kinetics and drug residence times of existing drugs or drug candidates [85]. Large amounts of computational drug repositioning methods choose transcriptomic data to identify potential new indications for drugs.…”

Section: Computational Approachesmentioning

confidence: 99%

Drug Repurposing in Neurological Diseases: Opportunities and Challenges

Mao¹

2020

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications

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Drug repurposing or repositioning refers to “studying of clinically approved drugs in one disease to see if they have therapeutic value and do not trigger side effects in other diseases.” Nowadays, it is a vital drug discovery approach to explore new therapeutic benefits of existing drugs or drug candidates in various human diseases including neurological disorders. This approach overcomes the shortage faced during traditional drug development in grounds of financial support and timeline. It is especially hopeful in some refractory diseases including neurological diseases. The feature that structure complexity of the nervous system and influence of blood–brain barrier permeability often becomes more difficult to develop new drugs in neuropathological conditions than diseases in other organs; therefore, drug repurposing is particularly of utmost importance. In this chapter, we discuss the role of drug repurposing in neurological diseases and make a summarization of repurposing candidates currently in clinical trials for neurological diseases and potential mechanisms as well as preliminary results. Subsequently we also outline drug repurposing approaches and limitations and challenges in the future investigations.

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Computational modeling approaches to quantitative structure–binding kinetics relationships in drug discovery

Cited by 19 publications

References 77 publications

Rapid Quantification of Protein-Ligand Binding via 19F NMR Lineshape Analysis

Rapid Quantification of Protein-Ligand Binding via 19F NMR Lineshape Analysis

In Silico Prediction of the Dissociation Rate Constants of Small Chemical Ligands by 3D-Grid-Based VolSurf Method

Drug Repurposing in Neurological Diseases: Opportunities and Challenges

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