Extracting ligands from receptors by reversed targeted molecular dynamics

Wolf, Romain M.

doi:10.1007/s10822-015-9863-2

Cited by 3 publications

(6 citation statements)

References 26 publications

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“…Compounds 9 and 11 show slow on and off binding kinetics. This finding prompted us to explore the most probable ligand unbinding pathways by carrying out targeted molecular dynamics (MD) simulations 21 for both 9 and 11 to evaluate whether the in silico calculated ligand resistance to dissociation would qualitatively correlate with the experimental k off . Molecular dynamics studies revealed the two most probable unbinding pathways (Figure 5A), which supported the findings of others in the nuclear receptor research field.…”

Section: ■ Results and Discussionmentioning

confidence: 92%

“…Interestingly, the ligand resistance to dissociation calculated via targeted MD simulations (i.e., the overall “action” S value to extract the ligand) was found to qualitatively correlate with experimental k off . Table reports the lowest S values for the unbinding pathways calculated 20 times for both compounds 9 and 11 .…”

Section: Resultsmentioning

confidence: 99%

“…Molecular dynamics studies revealed the two most probable unbinding pathways (Figure 5A), which supported the findings of others in the nuclear receptor research field. 22 Analyses of the dynamics of the protein without 9 bound with respect to Interestingly, the ligand resistance to dissociation calculated via targeted MD simulations (i.e., the overall "action" S value to extract the ligand 21 ) was found to qualitatively correlate with experimental k off . Table 3 reports the lowest S values for the unbinding pathways calculated 20 times for both compounds 9 and 11.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

et al. 2018

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The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.

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Section: ■ Results and Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

et al. 2018

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“…Wolf used a very similar approach when studying the ligand exit pathways of nuclear receptors by reversed TMD simulations. 61 He integrated the strain energy over the time of simulation to define a kind of "action" that is able to measure the effort required to the ligand exit. Wolf used this measure to evaluate the most probable unbinding pathways and hypothesized that this "action" can be qualitatively correlated to the k off value.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Estimation of Drug-Target Residence Time by Targeted Molecular Dynamics Simulations

Ziada

Diharce

Raimbaud

et al. 2022

J. Chem. Inf. Model.

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Drug-target residence time has emerged as a key selection factor in drug discovery since the binding duration of a drug molecule to its protein target can significantly impact its in vivo efficacy. The challenge in studying the residence time, in early drug discovery stages, lies in how to cost-effectively determine the residence time for the systematic assessment of compounds. Currently, there is still a lack of computational protocols to quickly estimate such a measure, particularly for large and flexible protein targets and drugs. Here, we report an efficient computational protocol, based on targeted molecular dynamics, to rank drug candidates by their residence time and to obtain insights into ligand−target dissociation mechanisms. The method was assessed on a dataset of 10 arylpyrazole inhibitors of CDK8, a large, flexible, and clinically important target, for which the experimental residence time of the inhibitors ranges from minutes to hours. The compounds were correctly ranked according to their estimated residence time scores compared to their experimental values. The analysis of protein−ligand interactions along the dissociation trajectories highlighted the favorable contribution of hydrophobic contacts to residence time and revealed key residues that strongly affect compound residence time.

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“…Some classical simulations can in fact be limited to the exploration of only certain energy landscape portions because of their sampling capabilities 44 . When using MD it is difficult to correctly and widely sample the useful landscape for structure transition and it becomes essential to use biased MD techniques [45][46][47] or other modified approaches such as supervised MD 48 . Using biased methods allow researchers to explore wide landscape of protein motions focusing on the energetic aspect of the allostery phenomenon.…”

Section: Allosteric Sitesmentioning

confidence: 99%

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

et al. 2018

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Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.

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Extracting ligands from receptors by reversed targeted molecular dynamics

Cited by 3 publications

References 26 publications

Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

Optimizing a Weakly Binding Fragment into a Potent RORγt Inverse Agonist with Efficacy in an in Vivo Inflammation Model

Estimation of Drug-Target Residence Time by Targeted Molecular Dynamics Simulations

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

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