Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations

Gentile, Francesco; Deriu, Marco Agostino; Licandro, Ginevra; Prunotto, Alessio; Danani, Andrea; Tuszyński, Jack A.

doi:10.3390/molecules20058316

Cited by 29 publications

(23 citation statements)

References 70 publications

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“…Among the top five poses obtained from the docking simulations, we identified one which showed a binding geometry similar to the R-837 pose obtained and validated in our previous study [ 22 ] ( Figure 3 A). The remaining four poses are reported in Figure S1.…”

Section: Resultssupporting

confidence: 80%

“…We have already reported the validation results for our TLR7 model in [ 22 ]. To summarize, the sequence identity between the TLR7 and TLR8 ectodomains was around 46%.…”

Section: Resultsmentioning

confidence: 99%

“…In this research, we explored the reverse process, i.e., we aimed to understand if compounds binding to the colchicine binding site in tubulin could possibly bind to the R-837 binding site at the interface between the two TLR7 monomers. Starting from our recent computational model of the human TLR7 model [ 22 ], we employed a series of in silico methods in order to identify and quantitatively characterize the binding mode of CR42-24 to the TLR7 site. We also employed a cell line-based experiment to demonstrate the possible interaction between the compound and TLR7, by studying the effect that CR-24-42 has on cancer cells carrying either a wild-type or a mutant TLR7 gene, respectively.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

et al. 2018

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The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications.

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Section: Resultssupporting

confidence: 80%

“…We have already reported the validation results for our TLR7 model in [ 22 ]. To summarize, the sequence identity between the TLR7 and TLR8 ectodomains was around 46%.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

et al. 2018

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“…Despite the large number of experimental studies focused on the AXH domain, a similar effort has not been put on the side of molecular modelling to investigate structural and dynamics of ATH m till now. However, molecular modeling, and in particular molecular dynamics has been widely demonstrated to provide important or even exceptional insights to better understand molecular mechanisms at the basis of subcellular phenomena, such as the ones that drive protein aggregation and protein misfolding in neurodegenerative diseases …”

Section: Introductionmentioning

confidence: 99%

Conformational fluctuations of the AXH monomer of Ataxin-1

et al. 2015

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In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.

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“…The physiological ligand of TLR7 is ssRNA . Its crystal structure is still not known, although a model based on the known TLR8 structure has been described. The signal transduction components are similar to TLR9, but differences in signaling strength have been found (Yu and Bauer, unpublished observation).…”

Section: Ervs In Mice With Defined Genetic Immune Impairmentmentioning

confidence: 99%

The potential role of retroviruses in autoimmunity

2015

Immunological Reviews

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In the last 20 years research in Immunology underwent fundamental changes. Most importantly, the identification of the key role of innate immune pattern recognition receptors (PRRs) that recognize evolutionarily conserved molecular patterns on infectious pathogens. This results in priming of innate immune cells, which in turn activate and direct the adaptive immune response. Progress in innate immune recognition instigated the current working hypothesis, that recognition of endogenous ligands by PRRs results in innate immune cell activation (autoinflammation) or activation of adaptive cells, with self-reactive antigen receptors (autoimmunity). In particular, nucleic acid-sensing innate immune receptors seem to be prime candidates for a mechanistic understanding of autoreactive activation of the immune system. However, it remains uncertain what the actual source of nucleic acid ligands is and what other signals are needed to drive activation of autoreactive innate immune cells and break self-tolerance of the adaptive immune system. Here, I will review our present understanding about whether the infection with exogenous retroviruses or the reactivation of endogenous retroviruses might play an etiological role in certain autoimmune conditions of humans and murine experimental models.

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Structure Based Modeling of Small Molecules Binding to the TLR7 by Atomistic Level Simulations

Cited by 29 publications

References 70 publications

A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

Conformational fluctuations of the AXH monomer of Ataxin-1

The potential role of retroviruses in autoimmunity

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