The nuclear factor kappa B (NFkB) modulates a broad range of cellular processes. NFkB pathway is stimulated by various signaling cascades and is involved in various cross-talks in the cell. NFkB controls the pro-inflammatory response by the TNFα and IL-1 signaling pathway. Inflammation is a defense mechanism of the body but when prolonged and chronic it results in various diseases, such as cancer, neurodegeneration, ageing, obesity, etc. NFkB pathway could be regulated at various levels to control chronic inflammation. As NFkB is involved in various cross-talks within the cell, a better understanding of the inter-linked pathway using computational modeling may introduce us with potential new drug targets. E3 ligases unlike other components of the pathway provide specificity, as it binds to the substrate molecule. Drugs designed to inhibit E3 ligase will ultimately choke the proteosomal degradation pathway and inhibit the NFkB pathway. This review provides the knowledge of the detailed NFkB pathway and its molecular mechanism. Also, we focused on computational modeling using deterministic and stochastic modeling methods in NFkB signaling pathway. This review also focuses on E3 ligases structure, function and inhibition by small-molecules as well as computational drug designing methods and their significance in finding new therapeutic candidates.