Discovery of the inhibitors of tumor necrosis factor alpha with structure-based virtual screening

Tumor necrosis factor alpha (TNF-alpha) has been considered as one of the attractive drug targets for allergic diseases including asthma. We have been able to identify five novel TNF-alpha inhibitors with a drug-design protocol involving the structure-based virtual screening and in vitro cell-based assay for antagonistic activity. Because the newly discovered inhibitors are structurally diverse and have the desirable physicochemical properties as a drug candidate, they deserve a further investigation as anti-asthmatic drugs. The interactions of the identified inhibitors in the binding site of TNF-alpha dimer are addressed in detail to understand the mechanisms for the stabilization of the inactive dimeric form of TNF-alpha. (C) 2010 Elsevier Ltd. All rights reserved.