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Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation.

ABSTRACT: Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied to screen new TNF-α inhibitors. Subsequently, multiple-docking protocols were used, and four-fold post-docking results were analyzed by consensus approach. After structure-based virtual screening, seventeen compounds were mutually ranked in top-ranked position by all the docking programs. Those identified hits target TNF-α dimer and effectively block TNF-α/TNFR interface. The predicted pharmacokinetics and physiological properties of the selected hits revealed that, out of seventeen, seven compounds (4, 5, 10, 11, 13-15) possessed excellent ADMET profile. These seven compounds plus three more molecules (7, 8 and 9) were chosen for molecular dynamics simulation studies to probe into ligand-induced structural and dynamic behavior of TNF-α, followed by ligand-TNF-α binding free energy calculation using MM-PBSA. The MM-PBSA calculations revealed that compounds 4, 5, 7 and 9 possess highest affinity for TNF-α; 8, 11, 13-15 exhibited moderate affinities, while compound 10 showed weaker binding affinity with TNF-α. This study provides valuable insights to design more potent and selective inhibitors of TNF-α, that will help to treat inflammatory disorders.

SUBMITTER: Halim SA

PROVIDER: S-EPMC7926523 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation.

Halim Sobia Ahsan SA Sikandari Almas Gul AG Khan Ajmal A Wadood Abdul A Fatmi Muhammad Qaiser MQ Csuk René R Al-Harrasi Ahmed A

Biomolecules 20210222 2

Tumor necrosis factor-α (TNF-α) is a drug target in rheumatoid arthritis and several other auto-immune disorders. TNF-α binds with TNF receptors (TNFR), located on the surface of several immunological cells to exert its effect. Hence, the use of inhibitors that can hinder the complex formation of TNF-α/TNFR can be of medicinal significance. In this study, multiple chem-informatics approaches, including descriptor-based screening, 2D-similarity searching, and pharmacophore modelling were applied ...[more]

PMID: 33671607

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Project description:ImportanceTumor necrosis factor α (TNF) inhibitor-induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor-induced psoriasiform eruptions in children.Design, setting, and participantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor-treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor-induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and relevanceIn this case series, paradoxical TNF inhibitor-induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.

Dataset Information

Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation.

Publications

Structure-Based Virtual Screening of Tumor Necrosis Factor-α Inhibitors by Cheminformatics Approaches and Bio-Molecular Simulation.

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