Identification of novel inhibitors for TNF?, TNFR1 and TNF?-TNFR1 complex using pharmacophore-based approaches.

ABSTRACT: BACKGROUND:Tumor necrosis factor ? (TNF?) is a multifunctional cytokine with a potent pro-inflammatory effect. It is a validated therapeutic target molecule for several disorders related to autoimmunity and inflammation. TNF?-TNF receptor-1 (TNFR1) signaling contributes to the pathological processes of these disorders. The current study is focused on finding novel small molecules that can directly bind to TNF? and/or TNFR1, preventing the interaction between TNF? or TNFR1, and regulating downstream signaling pathways. METHODS:Cheminformatics pipeline (pharmacophore modeling, virtual screening, molecular docking and in silico ADMET analysis) was used to screen for novel TNF? and TNFR1 inhibitors in the Zinc database. The pharmacophore-based models were generated to screen for the best drug like compounds in the Zinc database. RESULTS:The 39, 37 and 45 best hit molecules were mapped with the core pharmacophore features of TNF?, TNFR1, and the TNF?-TNFR1 complex respectively. They were further evaluated by molecular docking, protein-ligand interactions and in silico ADMET studies. The molecular docking analysis revealed the binding energies of TNF?, TNFR1 and the TNF?-TNFR1 complex, the basis of which was used to select the top five best binding energy compounds. Furthermore, in silico ADMET studies clearly revealed that all 15 compounds (ZINC09609430, ZINC49467549, ZINC13113075, ZINC39907639, ZINC25251930, ZINC02968981, ZINC09544246, ZINC58047088, ZINC72021182, ZINC08704414, ZINC05462670, ZINC35681945, ZINC23553920, ZINC05328058, and ZINC17206695) satisfied the Lipinski rule of five and had no toxicity. CONCLUSIONS:The new selective TNF?, TNFR1 and TNF?-TNFR1 complex inhibitors can serve as anti-inflammatory agents and are promising candidates for further research.

SUBMITTER: Saddala MS 

PROVIDER: S-EPMC6604280 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature