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

ABSTRACT: Tumor Necrosis Factor Alpha (TNF-?) 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-? 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-?, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-?. 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-?. 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-? 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.

SUBMITTER: Zia K

PROVIDER: S-EPMC7708426 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Zia Komal K Ashraf Sajda S Jabeen Almas A Saeed Maria M Nur-E-Alam Mohammad M Ahmed Sarfaraz S Al-Rehaily Adnan J AJ Ul-Haq Zaheer Z

Scientific reports 20201201 1

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 urg ...[more]

PMID: 33262408

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Project description:BackgroundPlasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.MethodsA sequence-based study was carried out using multiple sequence alignment, phylogenetic tree calculations and motif discovery analysis. Additionally, TKT models of PfTKT, PmTKT, PoTKT, PmTKT and PkTKT were modelled using the Saccharomyces cerevisiae TKT structure as template. Based on the modelled structures, molecular docking using 623 South African natural compounds was done. The stability, conformational changes and detailed interactions of selected compounds were accessed viz all-atom molecular dynamics (MD) simulations and binding free energy (BFE) calculations.ResultsSequence alignment, evolutionary and motif analyses revealed key differences between plasmodial and the human TKTs. High quality homodimeric three-dimensional PTKTs structures were constructed. Molecular docking results identified three compounds (SANC00107, SANC00411 and SANC00620) which selectively bind in the active site of all PTKTs with the lowest (better) binding affinity ≤ - 8.5 kcal/mol. MD simulations of ligand-bound systems showed stable fluctuations upon ligand binding. In all systems, ligands bind stably throughout the simulation and form crucial interactions with key active site residues. Simulations of selected compounds in complex with human TKT showed that ligands exited their binding sites at different time steps. BFE of protein-ligand complexes showed key residues involved in binding.ConclusionsThis study highlights significant differences between plasmodial and human TKTs and may provide valuable information for the development of novel anti-malarial inhibitors. Identified compounds may provide a starting point in the rational design of PTKT inhibitors and analogues based on these scaffolds.

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

Publications

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

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