Design and Structure-Guided Development of Novel Inhibitors of the Xeroderma Pigmentosum Group A (XPA) Protein–DNA Interaction

XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA–DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility. Furthermore, compound 1 analogs exhibited good specificity for XPA over RPA (replication protein A), another DNA-binding protein that participates in the nucleotide excision repair (NER) pathway. Importantly, there were no significant interactions observed by the X80 class of compounds directly with DNA. Molecular docking studies revealed a mechanistic model for the interaction, and these studies could serve as the basis for continued analysis of structure–activity relationships and drug development efforts of this novel target

Priority queueing models for cognitive radio networks with traffic differentiation

In this paper, we present a new queueing model providing the accurate average system time for packets transmitted over a cognitive radio (CR) link for multiple traffic classes with the preemptive and non-preemptive priority service disciplines. The analysis considers general packet service time, general distributions for the channel availability periods and service interruption periods, and a service-resume transmission. We further introduce and analyze two novel priority service disciplines for opportunistic spectrum access (OSA) networks which take advantage of interruptions to preempt low priority traffic at a low cost. Analytical results, in addition to simulation results to validate their accuracy, are also provided and illustrate the impact of different OSA network parameters on the average system time. We particularly show that, for the same average CR transmission link availability, the packet system time significantly increases in a semi-static network with long operating and interruption periods compared to an OSA network with fast alternating operating and interruption periods. We also present results indicating that, due to the presence of interruptions, priority queueing service disciplines provide a greater differentiated service in OSA networks than in traditional networks. The analytical tools presented in this paper are general and can be used to analyze the traffic metrics of most OSA networks carrying multiple classes of traffic with priority queueing service differentiation.Comment: 36 pages, 14 figures and 2 table