farPPI: a webserver for accurate prediction of protein-ligand binding structures for small-molecule PPI inhibitors by MM/PB(GB)SA methods

2018 ◽  
Vol 35 (10) ◽  
pp. 1777-1779 ◽  
Author(s):  
Zhe Wang ◽  
Xuwen Wang ◽  
Youyong Li ◽  
Tailong Lei ◽  
Ercheng Wang ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Small Molecule ◽  
Accurate Prediction

scholarly journals Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanan Liu ◽  
Canwei Wang ◽  
Jifa Li ◽  
Jiandong Zhu ◽  
Chengguang Zhao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ligand Binding ◽  
Fibroblast Growth Factor ◽  
Small Molecule ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Cancer Development ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth ◽  
Receptor Family

Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.

scholarly journals Ligands with poly-fluorophenyl moieties promote a local structural rearrangement in the Spinach2 and Broccoli aptamers that increases ligand affinities

2021 ◽  
Author(s):  
Sharif Anisuzzaman ◽  
Ivan M Geraskin ◽  
Muslum Ilgu ◽  
Lee Bendickson ◽  
George A Kraus ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Ligand Binding ◽  
Small Molecule ◽  
Binding Pocket ◽  
Structural Rearrangement ◽  
Structural Reorganization ◽  
Ligand Binding Pocket ◽  
Rna Remodeling ◽  
Small Molecule Ligands ◽  
Target Molecules

The interaction of nucleic acids with their molecular targets often involves structural reorganization that may traverse a complex folding landscape. With the more recent recognition that many RNAs, both coding and noncoding, may regulate cellular activities by interacting with target molecules, it becomes increasingly important to understand the means by which nucleic acids interact with their targets and how drugs might be developed that can influence critical folding transitions. We have extensively investigated the interaction of the Spinach2 and Broccoli aptamers with a library of small molecule ligands modified by various extensions from the imido nitrogen of DFHBI (3,5-difluoro-4-hydroxybenzylidene imidazolinone) that reach out from the Spinach2 ligand binding pocket. Studies of the interaction of these compounds with the aptamers revealed that poly-fluorophenyl-modified ligands initiate a slow change in aptamer affinity that takes an extended time (half-life of ~40 min) to achieve. The change in affinity appears to involve an initial disruption of the entrance to the ligand binding pocket followed by a gradual lockdown for which the most likely driving force is an interaction of the gateway adenine with a nearby 2'OH group. These results suggest that poly-fluorophenyl modifications might increase the ability of small molecule drugs to disrupt local structure and promote RNA remodeling.

Accurate Prediction of GPCR Ligand Binding Affinity with Free Energy Perturbation

2020 ◽  
Vol 60 (11) ◽  
pp. 5563-5579 ◽  
Author(s):  
Francesca Deflorian ◽  
Laura Perez-Benito ◽  
Eelke B Lenselink ◽  
Miles Congreve ◽  
Herman W. T. van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Accurate Prediction ◽  
Free Energy Perturbation ◽  
Energy Perturbation

scholarly journals A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology

PLoS ONE ◽  
2020 ◽  
Vol 15 (4) ◽  
pp. e0226661 ◽  
Author(s):  
Teresa L. Burgess ◽  
Joshua D. Amason ◽  
Jeffrey S. Rubin ◽  
Damien Y. Duveau ◽  
Laurence Lamy ◽  
...  
Keyword(s):  
Drug Development ◽  
Ligand Binding ◽  
Small Molecule ◽  
Binding Assay ◽  
Ligand Binding Assay ◽  
Small Molecule Drug

scholarly journals Label-free profiling of DNA aptamer-small molecule binding using T5 exonuclease

2020 ◽  
Vol 48 (20) ◽  
pp. e120-e120 ◽  
Author(s):  
Obtin Alkhamis ◽  
Weijuan Yang ◽  
Rifat Farhana ◽  
Haixiang Yu ◽  
Yi Xiao
Keyword(s):  
Ligand Binding ◽  
Small Molecule ◽  
High Throughput ◽  
Dna Aptamer ◽  
Label Free ◽  
General Applicability ◽  
Gold Standard Method ◽  
Characterization Methods ◽  
Increased Risk

Abstract In vitro aptamer isolation methods can yield hundreds of potential candidates, but selecting the optimal aptamer for a given application is challenging and laborious. Existing aptamer characterization methods either entail low-throughput analysis with sophisticated instrumentation, or offer the potential for higher throughput at the cost of providing a relatively increased risk of false-positive or -negative results. Here, we describe a novel method for accurately and sensitively evaluating the binding between DNA aptamers and small-molecule ligands in a high-throughput format without any aptamer engineering or labeling requirements. This approach is based on our new finding that ligand binding inhibits aptamer digestion by T5 exonuclease, where the extent of this inhibition correlates closely with the strength of aptamer-ligand binding. Our assay enables accurate and efficient screening of the ligand-binding profiles of individual aptamers, as well as the identification of the best target binders from a batch of aptamer candidates, independent of the ligands in question or the aptamer sequence and structure. We demonstrate the general applicability of this assay with a total of 106 aptamer-ligand pairs and validate these results with a gold-standard method. We expect that our assay can be readily expanded to characterize small-molecule-binding aptamers in an automated, high-throughput fashion.

scholarly journals Binding thermodynamics of host-guest systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

2019 ◽  
Author(s):  
David Slochower ◽  
Niel Henriksen ◽  
Lee-Ping Wang ◽  
John Chodera ◽  
David Mobley ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Force Field ◽  
Small Molecule ◽  
Force Fields ◽  
Free Energy Calculations ◽  
Model Systems ◽  
Conformational Space ◽  
Free Energies ◽  
Binding Thermodynamics ◽  
Binding Free Energies

<div><div><div><p>Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in small- molecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As model systems, host-guest complexes reduce many of the errors in more complex protein-ligand binding systems, as their small size greatly facilitates conformational sampling, and one can choose systems that avoid ambiguities in protonation states. These features, combined with their ease of experimental characterization, make host-guest systems ideal model systems to test and ultimately optimize force fields in the context of binding thermodynamics calculations.</p><p><br></p><p>The Open Force Field Initiative aims to create a modern, open software infrastructure for automatically generating and assessing force fields using data sets. The first force field to arise out of this effort, named SMIRNOFF99Frosst, has approximately one tenth the number of parameters, in version 1.0.5, compared to typical general small molecule force fields, such as GAFF. Here, we evaluate the accuracy of this initial force field, using free energy calculations of 43 α and β-cyclodextrin host-guest pairs for which experimental thermodynamic data are available, and compare with matched calculations using two versions of GAFF. For all three force fields, we used TIP3P water and AM1-BCC charges. The calculations are performed using the attach-pull-release (APR) method as implemented in the open source package, pAPRika. For binding free energies, the root mean square error of the SMIRNOFF99Frosst calculations relative to experiment is 0.9 [0.7, 1.1] kcal/mol, while the corresponding results for GAFF 1.7 and GAFF 2.1 are 0.9 [0.7, 1.1] kcal/mol and 1.7 [1.5, 1.9] kcal/mol, respectively, with 95% confidence ranges in brackets. These results suggest that SMIRNOFF99Frosst performs competitively with existing small molecule force fields and is a parsimonious starting point for optimization.</p></div></div></div>

scholarly journals A general strategy to construct small molecule biosensors in eukaryotes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Justin Feng ◽  
Benjamin W Jester ◽  
Christine E Tinberg ◽  
Daniel J Mandell ◽  
Mauricio S Antunes ◽  
...  
Keyword(s):  
Metabolic Engineering ◽  
Ligand Binding ◽  
Small Molecules ◽  
Small Molecule ◽  
Mammalian Cells ◽  
Fluorescent Protein ◽  
Dynamic Range ◽  
Plant Cells ◽  
General Strategy ◽  
Target Molecule

Biosensors for small molecules can be used in applications that range from metabolic engineering to orthogonal control of transcription. Here, we produce biosensors based on a ligand-binding domain (LBD) by using a method that, in principle, can be applied to any target molecule. The LBD is fused to either a fluorescent protein or a transcriptional activator and is destabilized by mutation such that the fusion accumulates only in cells containing the target ligand. We illustrate the power of this method by developing biosensors for digoxin and progesterone. Addition of ligand to yeast, mammalian, or plant cells expressing a biosensor activates transcription with a dynamic range of up to ~100-fold. We use the biosensors to improve the biotransformation of pregnenolone to progesterone in yeast and to regulate CRISPR activity in mammalian cells. This work provides a general methodology to develop biosensors for a broad range of molecules in eukaryotes.

scholarly journals Ligand Binding, Unbinding and Allosteric Effects: Deciphering Small Molecule Modulation of HSP90

2020 ◽  
Vol 118 (3) ◽  
pp. 46a
Author(s):  
Daniele Di Marino ◽  
Ilda D'Annessa ◽  
Stefano Raniolo ◽  
Vittorio Limongelli ◽  
Giorgio Colombo
Keyword(s):  
Ligand Binding ◽  
Small Molecule
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