Tumor necrosis factor-$alpha$ (TNF-$alpha$) exhibits cytotoxicity towards various tumor cells in vitro and induces apoptotic necrosis in transplanted tumors in vivo. It also shows severe toxicity when used systemically for the treatment of cancer patients, hampering the development of TNF-$alpha$ as a potential anticancer drug. In order to understand the structure-function relation of TNF-$alpha$ with respect to receptor binding, we selected four regions on the bottom of the TNF-$alpha$ trimer that are in close contact with the receptor and carried out mutagenesis studies and computational modeling. From the study, various TNF-$alpha$ muteins with a high therapeutic index were identified. These results will provide a structural basis for the design of highly potent TNF-$alpha$ for therapeutic purposes. By conjugating TNF-$alpha$ muteins with a high therapeutic index to a fusion partner, which targets a marker of angiogenesis, it could be possible to develop TNF-$alpha$ based anticancer drugs.