JAK3 differs from other JAK family members in terms of tissue distribution and functional properties, making it a promising target for autoimmune disease treatment. However, due to the high homology of these family members, targeting JAK3 selectively is difficult. As a result, exploiting small changes or selectively boosting affinity within the ATP binding region to produce new tailored inhibitors of JAK3 is extremely beneficial. PubChem CID 137321159 was used as the lead inhibitor in this study to preserve the characteristic structure and to collocate it with the redesigned new parent core structure, from which a series of 1,7-dihydro-dipyrrolo [2,3-b:3′,2′-e] pyridine derivatives were obtained using the backbone growth method. From the proposed compounds, 14 inhibitors of JAK3 were found based on the docking scoring evaluation. The RMSD and MM/PBSA methods of molecular dynamics simulations were also used to confirm the stable nature of this series of complex systems, and the weak protein–ligand interactions during the dynamics were graphically evaluated and further investigated. The results demonstrated that the new parent core structure fully occupied the hydrophobic cavity, enhanced the interactions of residues LEU828, VAL836, LYS855, GLU903, LEU905 and LEU956, and maintained the structural stability. Apart from this, the results of the analysis show that the binding efficiency of the designed inhibitors of JAK3 is mainly achieved by electrostatic and VDW interactions and the order of the binding free energy with JAK3 is: 8 (−70.286 kJ/mol) > 11 (−64.523 kJ/mol) > 6 (−51.225 kJ/mol) > 17 (−42.822 kJ/mol) > 10 (−40.975 kJ/mol) > 19 (−39.754 kJ/mol). This study may provide a valuable reference for the discovery of novel JAK3 inhibitors for those patients with immune diseases.
With increasing demands for more flexible services, the routing policies in enterprise networks become much richer. This has placed a heavy burden to the current router forwarding plane in support of the increasing number of policies, primarily due to the limited capacity in TCAM, which further hinders the development of new network services and applications. The scalable forwarding table structures for enterprise networks have therefore attracted numerous attentions from both academia and industry.To tackle this challenge, in this paper we present the design and implementation of a new forwarding table structure. It separates the functions of TCAM and SRAM, and maximally utilizes the large and flexible SRAM. A set of schemes are progressively designed, to compress storage of forwarding rules, and maintain correctness and achieve line-card speeds of packet forwarding. We further design an incremental update algorithm that allows less access to memory. The proposed scheme is validated and evaluated through a realistic implementation on a commercial router using real datasets. Our proposal can be easily implemented in the existing devices. The evaluation results show that the performance of forwarding tables under the proposed scheme is promising.
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