In silico pharmacogenetic approach: The natalizumab case study

Cavaliere, Francesca; Montanari, E.; Emerson, Andrew; Buschini, Annamaria; Cozzini, Pietro

doi:10.1016/j.taap.2017.07.011

Cited by 5 publications

(11 citation statements)

References 27 publications

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“…To note, in silico analysis already proved to be a reliable analytical tool to investigate the interaction of macromolecules with either small molecules (e.g., [20]) or other macromolecules, as shown already for InlA-Ecad [21]. Additionally, the computational assessment of inter-molecules interaction may eventually result in a reliable estimate of biological outcomes (e.g., [22][23][24][25]). Specifically, in the present work, a structure-based molecular modeling approach was developed and validated as a proof of concept using a set of previously characterized engineered mutations [9].…”

Section: Introductionmentioning

confidence: 88%

“…The possible effects of each mutation in terms of single-residue contribution to the InlA-Ecad interface interaction were investigated using the HINT scoring function as it previously succeeded to assess protein-protein complex formation and stability (e.g., [22]; see Section 2.3 for further details). As shown in Table 1, each InlA-Ecad interaction was qualitatively scored in accordance with the experimental data for all the complexes considered.…”

Section: Assessing the Effects Of Mutations On Interface Interactionmentioning

confidence: 99%

“…The capability of each mutation to affect the InlA-Ecad surface interaction was assessed and compared to the wt complex computing the overall interaction score of each complex with the HINT scoring function [26]. In particular, HINT score has an inverse relationship to the free energy of binding (the higher the score, the stronger the interaction expected) [34] and it previously proved reliable to compute protein-macromolecule complex formation (including protein-protein and protein-DNA complex) [22,35].…”

Section: Assessment Of Interface Interactionmentioning

confidence: 99%

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A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations

Dellafiora

Filipello

Dall’Asta

et al. 2020

Toxins

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Listeria monocytogenes is a widespread foodborne pathogen of high concern and internalin A is an important virulence factor that mediates cell invasion upon the interaction with the host protein E-cadherin. Nonsense mutations of internalin A are known to reduce virulence. Although missense mutations are largely overlooked, they need to be investigated in respect to their effects in cell invasion processes. This work presented a computational workflow to early characterize internalin A missense mutations. The method reliably estimated the effects of a set of engineered missense mutations in terms of their effects on internalin A–E-cadherin interaction. Then, the effects of mutations of an internalin A variant from a L. monocytogenes isolate were calculated. Mutations showed impairing effects on complex stability providing a mechanistic explanation of the low cells invasion capacity previously observed. Overall, our results provided a rational approach to explain the effects of internalin A missense mutations. Moreover, our findings highlighted that the strength of interaction may not directly relate to the cell invasion capacity reflecting the non-exclusive role of internalin A in determining the virulence of L. monocytogenes. The workflow could be extended to other virulence factors providing a promising platform to support a better molecular understanding of L. monocytogenes epidemiology.

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Section: Introductionmentioning

confidence: 88%

Section: Assessing the Effects Of Mutations On Interface Interactionmentioning

confidence: 99%

Section: Assessment Of Interface Interactionmentioning

confidence: 99%

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A Structural Study on the Listeria Monocytogenes Internalin A—Human E-cadherin Interaction: A Molecular Tool to Investigate the Effects of Missense Mutations

Dellafiora

Filipello

Dall’Asta

et al. 2020

Toxins

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“…At present, the mechanisms of resistance to natalizumab remains largely unknown. Recently, Cavaliere et al (28) applied molecular dynamics simulation to determine whether a polymorphism could induce conformational changes in VLA-4, affecting the binding affinity with natalizumab; expression profiling of circulating blood cells should be conducted for the identification of biomarkers of natalizumab resistance. The role of the genes identified in our study requires further investigation; however, certain genes may be involved in immunity and the pathology of MS.…”

Section: Discussionmentioning

confidence: 99%

Identification of CD4+ T cell biomarkers for predicting the response of patients with relapsing‑remitting multiple sclerosis to natalizumab treatment

et al. 2019

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of autoimmune etiopathogenesis, and is characterized by various neurological symptoms. Glatiramer acetate and interferon-β are administered as first-line treatments for this disease. In non-responsive patients, several second-line therapies are available, including natalizumab; however, a percentage of MS patients does not respond, or respond partially. Therefore, it is of the utmost importance to develop a diagnostic test for the prediction of drug response in patients suffering from complex diseases, such as MS, where several therapeutic options are already available. By a machine learning approach, the UnCorrelated Shrunken Centroid algorithm was applied to identify a subset of genes of CD4 + T cells that may predict the pharmacological response of relapsing-remitting MS patients to natalizumab, before the initiation of therapy. The results from the present study may provide a basis for the design of personalized therapeutic strategies for patients with MS.

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“…Some case studies have illustrated ligand-nuclear receptor (NR) interactions and their importance for multiple important diseases or toxicological purposes. For instance: i) bisphenols, molecules used to produce plastics against estrogen and androgen receptors, of interest for cancer (Cavaliere et al, 2020), ii) Daphnia magna and RXR for water environment control, iii) in vivo test reduction for multiple sclerosis (Cavaliere et al, 2017).…”

Section: Meeting Reportmentioning

confidence: 99%