Identification of potential TNF-α inhibitors: from in silico to in vitro studies

Abstract

Tumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC50 32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.

Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro

“…Intracochlear inflammation and hair cell damage are associated with TNF-α expression [ 36 ]. The TNF-α reduction assay is commonly used to investigate anti-inflammatory potential of therapy strategies [ 37 ]. In this assay, cells are stressed by adding LPS (Sigma-Aldrich, St. Louis, MO, USA) and produce, in response to the stress, TNF-α.…”

In-silico evaluation of Fragransol B from Myristica dactyloides for anti-inflammatory potential

“…Several earlier studies have set an XP value greater than −6.5 kcal/mol as a cut-off score for further experimental consideration of the molecule as a drug candidate (Table 3 and Fig. 6) (Zia et al, 2020). Thus, our results highlight the possible role of Fragransol B in treating diseases influenced by the dysregulation of TNF-α.…”

“…Finding new inhibitor molecules for TNF-α has considerable therapeutic potential in treating various diseases including cancer (Zia et al, 2020). Our analysis recorded an XP score of −6.347 kcal/mol for the interaction of Fragransol B with this target protein.…”

Accelerated Discovery of Potent Bioactive anti‐TNFα Aptamers by Microbead‐Assisted Capillary Electrophoresis (MACE)‐SELEX

“…To date, five biologics targeting TNFα have been approved, including the anti-TNFα monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein of TNFR-antibody Fc etanercept (Enbrel), [5] although no smallmolecule inhibitor has been clinically approved. [6,7] Because biologics exhibit high efficacy and systematic protection against bone and cartilage erosion, these biologics are currently the most reliable therapy for RA patients. However, the high cost, heterogeneous manufacturing, immunogenic property, and relatively short storage of these biologics are considerable drawbacks.…”