Proposing novel TNFα direct inhibitor Scaffolds using fragment-docking based e-pharmacophore modeling and binary QSAR-based virtual screening protocols pipeline

Journal of Molecular Graphics & Modelling
Mehreen ZakaSerdar Durdagi

Abstract

Tumor necrosis factor alpha (TNFα) is a homotrimer protein that plays a pivotal role for critical immune functions, including infection, inflammation and antitumor responses. It also plays a primary role in autoimmune diseases like rheumatoid arthritis (RA). So far, only biological therapeutics like infliximab, etanercept, and adalimumab are available as treatment of inflammatory diseases. They directly bind to TNFα and interrupt its binding to its receptor protein tumor necrosis factor receptor (TNFR). However, they may also cause serious side effects such as activating an autoimmune anti-antibody response or the weakening of the body's immune defenses. Thus, small molecule-based therapies can be considered as alternative methods. In this study, a novel method is applied to develop energetically optimized, structure-based pharmacophore models for rapid in silico drug screening. Fragment-based docking results were used in the construction of an universal e-pharmacophore model development. The developed model is then used for screening of small-molecule library Specs-screening compounds (Specs-SC) which includes more than 200.000 drug-like molecules. In another approach, binary QSAR-based models were used to screen Specs-SC, as ...Continue Reading

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